Antifungals

ANTI-FUNGAL
AGENTS
Prepared By
DOPPALAPUDI SANDEEP
M. Pharmacy,
Assistant Professor
Department of Physiology & Pharmacology
Chebrolu Hanumaiah Institute of Pharmaceutical
Sciences, Chandramoulipuram, Chowdavaram, Guntur,
Andhra Pradesh, India – 522019

CLASSIFICATION
• Antibiotics:
 Polyenes - Amphotericin B, Nystatin, Hamycin
 Heterocyclic benzofuran - Griseofulvin
• Antimetabolite - 5-Flucytosine
• Allylamine - Terbinafine
• Azoles:
• A. IMIDAZOLES
I. TOPICAL - Clotrimazole
Econazole
Miconazole
II. SYSTEMIC - Ketoconazole
• B. TRIAZOLES
I. SYSTEMIC - Fluconazole
Itraconazole
• Others: Undecylenic acid, benzoic acid, tolnaftate

• Extracted from “Penicillium griseofulvum”.
• Active against dermatophytes.
Eg: epidermophyton, trichophyton, microsporum
• Not active against Candida.
• Dermatophytes actively concentrate it-selective toxicity.
• It doesn’t has any anti-bacterial activity.
• It is FUNGISTATIC but not fungicidal.
GRISEOFULVIN

• Interferes with MITOSIS.
• Causes abnormal metaphase configurations.
• The daughter nuclei fail to move apart or move only a
short distance.
• As a result, multi-nucleated and stunted fungal hyphae
occurs.
• Disorients the microtubules (pulls chromosomes apart).
MECHANISM OF ACTION

• Absorption: Irregular due to low water solubility.
• It can be improved by taking it with fats and by
microfining the drug particles.
• Deposited in keratin forming cells of skin, hair and nails.
• Newly formed keratin is not invaded by fungus, but the
fungus which persists in already infected keratin, till it
sheds off.
• It persists for weeks in skin and keratin.
PHARMACOKINETICS

• Very low.
• Headache is the commonest complaint.
• G.I.T disturbances are observed.
• Discontinuation – if Rashes, Photoallergy was
observed.
• USES:
• Used systemically only for dermatophytosis.
ADVERSE EFFECTS & USES

• 125 – 250 mg QID with meals.
• Duration of Treatment depends upon Site of infection, Thickness of infected
keratin and Turnover rate.
• Body skin – 3 weeks
• Palm, soles - 4 – 6 weeks
• Finger nails - 4 – 6 months
• Toe nails - 8 – 12 months
• INTERACTIONS:
• Induces warfarin metabolism.
• Reduces efficacy of oral contraceptives.
• Failure of therapy with phenobarbitone.
• Causes intolerance to alcohol.
DOSES & INTERACTIONS

• Extracted from “Streptomyces nodosus”.
• Chemistry:
• contains macrocyclic ring- one side has several conjugated
double bonds (highly lipophilic) and other side with many
OH groups (hydrophilic).
• Selectivity of AMB is low.
• also effects cholesterol in human cell membrane due to
structural resemblence with ergosterol.
• Active against wide range of yeast and fungi.
• DOSE: 50-100 mg QID
AMPHOTERICIN-B

• AMB has high affinity with ergosterol in fungal cell wall.
• combines with it, gets inserted into membrane and several
AMB molecules orient together to form a micropore.
• hydrophilic side forms interior through which water, ions,
aminoacids move out.
• micropore is stabilized by sterols of AMB.
• This leads to increased cell permeability.
• AMB enhaces immunity in animals
MECHANISM OF ACTION

• Absorption: Not absorbed. Can be given orally for
intestinal candidiasis without systemic toxicity.
• IV suspension is taken made with deoxycholate-widely
distributed.
• Poor CSF penetration.
• Binds to sterols in body tissues and stays for longer
periods.
• Half life-15 days. metabolized in liver.
• Excretes slowly through urine and bile.
PHARMACOKINETICS

• Acute reaction: chills, aches, fever,
Nausea,vomiting, dyspnea.
• Thrombophlebitis.
• nephrotoxicity-long term
• Reduced GFR, acidosis, hypokalemia
• Anaemia, CNS toxicity
• USES: for oral, vaginal and cutaneous candidiasis,
leishmaniasis.
ADVERSE EFFECTS & USES

• 5-FLUCYTOSINE:
• Pyrimidine antimetabolite, inactive as such.
5-FC
taken up by fungal cells & converted to
5-Fluorouracil
Converted to
5- Fluorodeoxyuridylic acid
(INHIBITS thymidilate synthesis)
No DNA formation in fungal cell
ANTIMETABOLITES

• Mammalian cells have low capacity to convert 5-FC to 5-FU. So
fungal selectivity action occurs.
• Active against Cryptococcus, Torula and few strains of Candida.
• ADVERSE EFFECTS:
1. Leucopenia
2. thrombocytopenia
3. bone marrow depression
4. G.I disturbaces
5. Diarrhoea in some cases
6. Mild liver dysfunction – reversible.
• USES: Not used as a SOLE therapy.
• Used in cryptococciasis with Amphotericin-B.
5 - FLUCYTOSINE

• Currently most extensively used antifungals.
• They have broad spectrum activity. Effective against
dermatophytes, Candida, Nocardia, Staph. aureus, Strept. faecalis,
Bac. fragilis and Leishmania.
• Mechanism of action: AZOLES
INHIBITS
ERGOSTEROL
Membrane abnormalities in fungus
DEATH OF FUNGUS
AZOLE ANTIFUNGALS
LANOSTEROL 14-DEMETHYLASE

• Effective in topical treatment of tinea infections – 60 to 100% cure
rates with 2 – 4 weeks application on a twice daily schedule.
• Effective for athletes foot,
otomycosis,
oral, cutaneous, vaginal candidias.
• Mostly for vaginitis due to long lasting residual effect after one
application.( 7 day course)
• For oropharyngeal candidias, 10mg in mouth 3-4 times a day
• Well tolerated
• Local irritation with burning sensation occurs sometime
CLOTRIMAZOLE

• ECONAZOLE:
• Similar to clotrimazole. Effectively penetrates through skin.
• Highly effective in dermatophytosis, otomycosis, oral thrush, but somewhat
inferior to clotrimazole in vaginitis.
• NO adverse effects. Local irritation in a few was reported.
• 1% ointment & 150 mg vaginal tab.
• MICONAZOLE:
• Highly efficacious drug (>90% cure rate) for tinea, cutaneous and vaginal
candidias, otomycosis.
• Has very good penetrating power. Even single application on skin acts for few days.
• A higher evidence of vaginal irritation was reported.
• 2% gel & 2% powder solution.
ECONAZOLE & MICONAZOLE

• First ORALLY effective broad spectrum antifungal drug.
• Oral absorption is facilitated by gastric acidity, as it is soluble at lower pH.
• Larger binding to albumin, extensive hepatic metabolism, excretion in
urine and faeces.
• A short t1/2 - 11/2 to 6 hours.
• DOSE: 200 mg OD or BD.
• Nausea, vomiting – reduced by taking with meals.
• Loss of appetite, headache, rashes and hair loss.
• Decreases androgen production (testosterone) in men. It results in
gynaecomastia, loss of hair and libido.
• Menstrual irregularities in women due to suppression of estradiol
synthesis.
• Contraindicated in pregnants and nursing women.
KETOCONAZOLE (KTZ)

• DRUG INTERACTIONS:
• Antacids – Decreases oral absorption.
• Rifampicin, phenobarbitone, Phenytoin – Induces metabolism
• Warfarin, diazepam, sulfonyl ureas – Increased concentration.
(due to inhibition of CytP450 by Ketoconazole)
 Terfenadine, cisapride – Induces Ventricular tachycardia, fatal
ventricular fibrillation.
 USES:
 In dermatophytosis – concentrated in stratum corneum.
 High doses are used in Cushing’s syndrome.
 Fluconazole and itraconazole have replaced the KTZ largely due to their lesser side
effects, toxicity (lower affinity for mammalian CytP450) and higher efficacy.
KETOCONAZOLE

• Newer water soluble triazole having wide range of activity than KTZ.
• Mostly used in crpytococcal meningitis, systemic and mucosal candidiasis.
PREFERRED drug fro Fungal Meningitis.
• Doesn’t inhibit the steroid synthesis –NO Antiandrogenic effect.
• PHARMACOKINETICS:
• 94% absorbed- Oral BA is not affected by food or gastric pH.
• Excreted unchanged in urine. T1/2 is 25-30 hrs.
• Fungicidal concentrations are achieved in Nails, vagina and saliva.
• Penetration into Brain and CSF is good.
• Dose reduction is needed in renal impairment.
• Nausea, vomiting, abdominal pain, rash, headache.
• NOT recommended in pregnant women and lactating mothers.
FLUCONAZOLE

• Increases plasma levels of phenytoin, cisapride, warfarin, zidovudine, etc.
• With cisapride – produces ventricular tachycardia.
• USES:
• In vaginal candidiasis – 150 mg p.o
• Tinea and cutaneous infections – 150 mg weekly for 4 weeks
• Cryptococcal meningitis – 200-400 mg/day for 4-12 weeks
• Fungal keratitis – eye drops (0.3%).
• It is Longer acting,
Safer and
More efficacious than KTZ.
FLUCONAZOLE

• Has Broad spectrum activity than KTZ or Fluconazole.
• It is fungistatic.
• NO steroidal hormone inhibition or hepatotoxicity.
• Oral absorption is enhanced by food and gastric acid.
• High protein bound.
• Accumulates in vaginal mucosa, skin and nails. Poor CSF entry.
• High metabolism. Excreted in faeces.
• Dizziness, pruritis, headache and hypokalemia.
• Unsteadiness and impotence are infrequent.
ITRACONAZOLE

• Antacids – Reduces oral absorption.
• Phenytoin, rifampicin, Phenobarbitone – Induces metabolism
• Warfarin, digoxin – concentration in plasma increases.
• Cisapride – induces Ventricular arrhythmias.
• USES:
• Drug of choice for chromomycosis and paracoccidiomycosis.
• In aspergillosis – 200mg OD/BD with meals for 3 months.
• Vaginal candidiasis – 200 mg OD for 3 days.
• Dermatophytosis - 100 – 200 mg OD for 7 – 15 days.
 Onchomycosis - 200 mg/day for 3 months.
ITRACONAZOLE

• An allylamine – orally and topically active against candida and
dermatophytes (1st line drug).
• It is fungicidal. More efficacious than griseofulvin, itraconazole.
TERBINAFINE
INHIBITS
Squalene deposits in fungi
NO ERGOSTEROL SYNTHESIS
FUNGICIDAL ACTION
TERBINAFINE
SQUALENE EPOXIDASE

• 75% is absorbed. FIRST PASS metabolism reduces Oral BA.
• Lipophilic, widely distributed in body.
• Concentrated in sebum, stratum corneum and nail plates.
• Mostly excreted in urine. Less through faeces.
• SIDE EFFECTS:
• Gastric upset, rashes, taste disturbance.
• Topical route causes erythema, itching, dryness, irritation and rashes.
• Enzyme inducers lower and enzyme inhibitors raise the steady state plasma levels
of terbinafine.
• USES:
• Topically 1% cream or Orally 250 mg OD in case of Tinea infections. 2 to 6 weeks
treatment depending upon site.
• Onchomycosis – 3 to 12 months oral therapy.
TERBINAFINE

• TOLNAFTATE:
• Effective drug for Tinea cruris and T. corporis.(1-3 weeks)
• Poor penetrability – Less effective in T. capitis (scalp) T. unguium (nails). Relapses
are common. Not effective in candidiasis.
• Salicylic acid is used along for keratolytic action.
• Causes little irritation. Inferior in action to imidazoles.
• UNDECYLENIC ACID:
• Fungistatic. Used topically in combination with Zinc salt.
• Lower cure rates even after prolonged treatment.
• Still used for T. pedis, nappy rashes and T. cruris.
• BENZOIC ACID: (RING CUTTER ointment)
• Fungistatic. Needs prolonged application till keratin sheds off
• In Hyperkeratotic lesions, used with salicylic acid as WHITFIELDS OINTMENT
(Benzoic acid-5% and Salicylic acid- 3%).
• Salicylic acid helps to remove the infected tissue and promotes penetration of
benzoic acid into the lesion.
• Irritation and burning sensation occurs
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