R.GAYATHRI DEVIPHARM D

Antifungal DrugsAntifungal Drugs

Introduction - Introduction - Also called Also called antimycotic drugsantimycotic drugsUsed to treat two types of fungal

infection:◦ Superficial fungal infections - skin or mucous

membrane◦ Systemic fungal infections - lungs or central

nervous systemFungi causing mycosis live as

commensally or are present in the environment.

Earlier superficial infections were common and systemic rather rare.

Recently there is increase in local as well as systemic fungal infections.

Reason for this is opportunistic infections

Opportunistic infectionsOpportunistic infectionsImmuno-suppression due to

- Cancer chemotherapy- AIDS◦Corticosteroid overuse

Indiscriminate use of broad spectrum antibiotics

Fungal infectionsSuperficial

◦ Skin◦ Hair◦ Nails◦ Mucous

membrane

Deep◦ Tissues (muscle &

connective tissue)◦ Organs

Images of some superficial skin infectio

ns

Types of fungal infections - Types of fungal infections - MycosesMycosesSuperficial mycoses

◦ Affect the skin, hair and nails – ringworm/tinea or onychomycosis

Subcutaneous mycoses (tropical)◦ Affect the muscle and connective tissue

immediately below the skinSystemic (invasive) mycoses

◦ Involve the internal organsAllergic mycoses

◦ Affect lungs or sinuses ◦ Patients may have chronic asthma, cystic fibrosis or

sinusitisThere is some overlap between these

groups

MOST COMMON FUNGAL MOST COMMON FUNGAL PATHOGENSPATHOGENSDermatophytes – Microsporum,

Epidermophyton and Trichophyton

Candida – C. albicans, C. glabrata, C. tropicalis

AspergillusCryptococcusRhizopus

Causative fungiCausative fungiSuperficial infections by

◦Dermatophytes (ring worms): athlete`s foot or tinea pedis, jock itch or tinea cruris, tinea capitis etc.

◦Candida: oral thrush, vaginitis and diaper candidiasis etc.

Deep infections are◦Candidiasis: Chronic mucocutaneous

candidiasis, systemic candidiasis etc.◦Aspergillosis: broncho-pulmonary

aspergillosis◦Coccidiomycosis: pulmonary and

disseminated (complications – pneumonia)◦Histoplasmosis: H. capsulatum (common in

HIV)

What are the targets for antifungal What are the targets for antifungal therapy?therapy?

Cell membraneFungi use principally ergosterol instead of cholesterol

Cell WallUnlike mammalian cells, fungi have a cell wall

DNA SynthesisSome compounds may be selectively activated by fungi, arresting DNA synthesis.

Polyene antibiotics-Polyene antibiotics-Amphotericin BAmphotericin B

Fermentation product of Streptomyces nodusus High affinity for ergosterol present in fungal cell

membrane Hydrophilic polyhydroxyl chain along one side and a

lipophilic polyene hydrocarbon chain on the other Binds sterols in fungal cell membrane –

◦ high affinity for ergosterol present in fungal cell membrane◦ affinity is less for host cell membrane although closely

resembles Creates transmembrane channel and electrolyte

leakage. Active against most fungi except Aspergillus terreus,

Scedosporium spp. Bacteria lack sterols so insensitive to polyenes

Cell Membrane Active Cell Membrane Active AntifungalAntifungal

Cell membrane1. Polyene antibiotics - Amphotericin B, lipid

formulations - Nystatin (topical)

2. Azole antifungals Imidazoles:

• Topical: Clotrimazole, econazole, miconazole

• Systemic: KetoconazoleTriazoles: Fluconazole,

itraconazole and voriconazole

Antifungal spectrumAntifungal spectrumMost Toxic antifungalFungicide at high and static at

low conc.Effective against

◦Candida albicans◦Histoplasma capsulatum◦Cryptococcus

PharmacokineticsPharmacokinetics Insoluble in waterUnstable at 37degreePoorly absorbed from GITCannot cross BBBHighly bound to plasma proteinsTakes 2 months for complete clearance of

drugGiven as I/V infusionFor fungal meningitis given intrathecallyHas immuno-stimulant action alsoGiven in immuno-compromised patients for

fungal infections

UsesUsesBroad spectrum antifungalUseful for1. Candida that causes

◦ oral◦ vaginal◦ cutaneous candidiasis

2. Cryptococcus3. Histoplasma4. Aspergillosis5. Also effective for Leishmaniasis(Reserve

drug for resistant cases of Kala Azar)

ADRsADRs1. Acute reactions - occurs with each

infusion◦ Chills, Nausea, Vomiting, Pain, Fever, Aches, Dyspnoea◦ So corticosteroids are administered along with the drug

2. Thrombophlebitis3. Bone marrow depression - Reversible

anemia4. On intrathecal injection – Headache,

Vomiting, Nerve paralysis5. Renal toxicity leading to – Azotemia,

Decreased GFR, Acidosis, Hypokalemia, Inability to conc. urine

Newer Amphotericin BNewer Amphotericin BThey are developed to overcome1. Side effects2. To improve tolerability3. To get the drug at site of action4. To reduce the toxicity i.e.. Less nephrotoxic

and minimal anemiaFormulations are:1. Amphotericin B lipid complex2. Amphotericin B colloidal dispersion3. Liposomal Amphotericin B(Only drawback of these formulations is less

efficacy)

Drug Interactions of Drug Interactions of Amphotericin BAmphotericin BWith Flucytocin-synergistic actionRifampicin and Minocyclin –

◦ Both potentiate Amphotericin BVancomycin and Aminoglycoside –

◦ Both increase risk of nephrotoxicityPreparation and doses:

◦ 50 – 100 mg four times a day orally◦ 3% ear drops◦ Systemic: 50 mg vial (one vial diluted in

500 ml of 5% glucose and initially 1 mg test dose followed by infusion for 4 – 8 Hrs)

NystatinNystatinSimilar to Amphotericin B but more

toxic than Amphotericin BUsed only for superficial candidiasis ofSkin, Mouth, Vagina, IntestineAs ointment ,oral tablets &

suppositoriesAvailable as tablets and ointments (1

to 5 lacs U) – also vaginal tabletsOrally not absorbed but can be used in

monilial diarrhoea

Other PolyenesOther PolyenesHamycin:Water solubleAbsorption from GIT not reliableNot used for systemic fungal

infectionsUsed topically for Aspergillus,

Candida, Monilial, Trichomonas vaginalis infections

Natamycin:Broad spectrumUsed topically for – Keratitis, Monilial

infections, Trichomonas vaginalis

Imidazoles and TriazolesImidazoles and TriazolesAzole antifungals Imidazoles:

◦ Topical: Clotrimazole, econazole, miconazole

◦ Systemic: KetoconazoleTriazoles: Fluconazole,

itraconazole and voriconazoleRemember that among imidazoles,

only ketocanazole is systemic, other 3 are topical only

While, Triazoles are used systemically and largely replacing ketoconazole

Azole StructuresAzole Structures

Fluconazole Ketoconazole

Azoles Azoles – Common – Common MechanismMechanism

• In fungi, the cytochrome P450-enzyme lanosterol 14-alpha demethylase is responsible for the conversion of lanosterol to ergosterol

• Azoles bind to lanosterol 14α-demethylase inhibiting the production of ergosterol– Some cross-reactivity is seen with

mammalian cytochrome p450 enzymes leading to

• Drug Interactions• Impairment of steroidneogenesis

(ketoconazole, itraconazole)

Individual AgentsIndividual AgentsKetoconazole:Spectrum: yeasts and moulds - poor

absorption limits its role for severe infections, generally used in mucosal infections only (dematophytosis)

Pharmacokinetics◦ Variable oral absorption, dependent on pH

(often given with cola or fruit juice)◦ T1/2 = 7-10 hours◦ Protein binding > 99%◦ Hepatic, bile and kidney elimination

Ketoconazole – contd.Ketoconazole – contd.Adverse effects

◦N&V, worse with higher doses (800 mg/day)

◦Hepatoxicity (2-8%), increase in transaminases, hepatitis

◦Dose related inhibition of CYP P450 responsible for testosterone synthesis Gynecomastia, oligosperma, decreased libido

◦Dose-related inhibition of CYP P450 responsible for adrenal cortisol synthesis

Ketoconazole – contd.Ketoconazole – contd.Drug Interaction:Potent inhibitor of cytochrome P450 3A4

◦ Rifampin and phenytoin decrease ketoconazole levels

◦ Ketoconazole increases cyclosporin, warfarin, astemizole, corticosteroid, and theophylline levels

Many of these drug interactions are severe

Drugs that increase gastric pH will decrease blood levels of ketoconazole◦ Antacids, omeprazole, H2 blockers

Doses: ◦ Serious infections 800 mg/day PO◦ Other: 200-400 mg/day PO

FluconazoleFluconazoleWater soluble having wider range of activity

than KetoconazoleGood activity against C. albicans and

Cryptococcus neoformansNon-albicans Candida species more likely to

exhibit primary resistance

Always resistant Sometimes resistant

C. krusei > C. glabrata > C. parapsilosis

C. tropicalis

C. kefyr

ResistanceResistancePrimary resistance (seen in severely

ill or immunocompromised patients)◦ Selection of resistant species or

subpopulations◦ Replacement with more resistant strain

Secondary resistance (seen in patients with AIDS who experienced recurrent orophayrngeal candidiasis and received long-term fluconazole therapy)◦ Genetic mutation◦ Upregulation of efflux pumps

Mechanisms of antifungal Mechanisms of antifungal resistanceresistance

Target enzyme modification

Ergosterol biosynthetic pathway

Efflux pumpsDrug import

Fluconazole - KineticsFluconazole - Kinetics Available as both IV and PO

◦ Bioavailibility > 90% Pharmacokinetics

◦ t 1/2 = ~24 hours◦ Protein binding < 12%◦ Vd 0.85 L/kg (widely distributed)◦ >90% excreted unchanged through the kidney

Dosing1. Mucosal candidiasis

100-200 mg/day (150 mg tablet vulvovaginal candidiasis)2. Systemic fungal infections

400-800 mg q24h > 800 mg q24h in unstable patient, S-DD isolate, or if non-

albicans spp. (except C. krusei)3. Maintenance for cryptococcal meningitis

400 mg q24h

Fluconazole - ADRsFluconazole - ADRsN&V, rash:

◦More likely with high doses and in AIDS patients

◦Asymptomatic increase in LFTs (7%)Drug interactions:

◦May increase phenytoin, cyclosporin, rifabutin, warfarin, and zidovudine concentrations

◦Rifampin reduced fluconazole levels to half (even though FLU is not a major

substrate)

ItraconazoleItraconazole

Some Features:Newer orally active triazoleBroader spectrun than KTZ and FCZ

– includes moulds like aspergillusFungistatic action but very effective

in immunocompromizrd patientsSteroid hormone synthesis

inhibition is absent and no serious hepatotoxicity

KetoconazoleKetoconazole FluconazoleFluconazole ItraconazoleItraconazole

11 Broad spectrumBroad spectrum Still wider rangeStill wider range Fungi staticFungi static

22 DermatophyteDermatophyte

& deep mycosis& deep mycosis

Cryptococcal & coccidialCryptococcal & coccidial

meningitismeningitis

immunocompromisedimmunocompromised

patientspatients

33 Absorbed at low pHAbsorbed at low pH Good oral absorptionGood oral absorption Varies with food & pHVaries with food & pH

44 Highly bound to PPHighly bound to PP Not muchNot much Highly boundHighly bound

55 More S/E, headache, androgenMore S/E, headache, androgen

inhibitioninhibition

Less S/E, headache & rashLess S/E, headache & rash Hypokalemia, pruritis &Hypokalemia, pruritis &

dizzinessdizziness

66 Causes hepatic impairmentCauses hepatic impairment MildMild Not hepatotoxicNot hepatotoxic

77 Inhibit cytochrome P450Inhibit cytochrome P450 Inhibit only fungal P450Inhibit only fungal P450 No effectNo effect

88 Used for Monilial vaginitis. Used for Monilial vaginitis.

Cushing’s synCushing’s syn

Candidiasis, Keratitis, Candidiasis, Keratitis,

Cryptococcal meningitisCryptococcal meningitis

Mycosis, meningitis Mycosis, meningitis

Chromo & paracocciChromo & paracocci

Local azolesLocal azolesVery popular local azoles are – Clotrimazole,

Econazole and Miconazole (For Tinea, Ring worm, Athlete’s foot,

otomycosis, oral, cutaneous & vaginal candidiasis)

Mechanism of action is same as that of Ketoconazole i.e. ergosterol inhibition by inhibiting CYP450

Clotrimazole is favoured in vaginitis because of long lasting residual effect and once daily dosing

Miconazole causes frequently vaginal irritation & pelvic cramp.

Available s lotion, cream, powder, vaginal tablet etc.

Heterocyclic Nitrofurans - Heterocyclic Nitrofurans - GriseofulvinGriseofulvinUsed for superficial fungal infections

by dermatophytesDerived from Penicillium griseofulvum

but no antibacterial activityEffective against most

dermatophytes, but not against candida causing deep mycosis

Dermatophytes actively concentrate it – accounts for selective toxicity against them

Taken up by newly formed keratin

Griseofulvin - MOAGriseofulvin - MOA

Interferes with mitosis – results in multinucleated and stunted hyphae

(In most fungi, hyphae are the main mode of vegetative growth, and are collectively called a mycelium yeasts are unicellular fungi that do not grow as hyphae)

Abnormal metaphase configurations leading to failure of daughter nuclei to fall apart

(Colchicine and vinca alkloids also mitotic inhibitors but they cause arrest of mitosis)

Disorientation of polymerized microtubules

Griseofulvin – contd.Griseofulvin – contd.Pharmacokinetics:Given orally and fats improve absorptionAbsorption depends on the particle sizeDuration of treatment depends upon tissue

turn over 1. 3-6 wks for skin & hair 2. 3-6 months for nailsTreatment should continue till whole infected

tissue is shed off.Doses: Used orally only for dermatophytosis

(125 to 250 mg 4 times daily, but depends on site of infection

Griseofulvin - ADRsGriseofulvin - ADRsSafe with mild side effects 1. GIT upsets 2. CNS symptoms 3. Hepatotoxicity 4. Leucopenia 5. Photosensitivity 6. Allergy etc.Microsomal enzyme inducerCauses decrease in activity of anticoagulantsCause intolerance to alcoholPhenobarbitone reduces its oral absorption

so failure of therapy

FlucytosinFlucytosin Fluorinated pyrimidine related to flurouracil Restricted spectrum of activity. Acquired Resistance due to > result of monotherapy Due to: 1) Decreased uptake (permease activity) 2) Altered 5-FC metabolism (cytosine deaminase or

UMP pyrophosphorylase activity)

Kinetics: Orally absorbed Widely distributed even in CSF Exc. in urine. Converted in fungal cell to 5-FU which is

antimetabolite. Mammalian cells remain unaffected except few bone

marrow cells

FlucytosinFlucytosinMonotherapy : Never

Candidiasis Candidiasis CryptococcosisCryptococcosis

AspergillosisAspergillosis } In combination with amphotericin B or

fluconazole.

Doses:1. Vaginal candidiasis: 200 mg OD for 3 days2. Dermatophytosis; 100-200 mg OD for 7-15 days3. Onychomycosis: 200 mg per day for 3 monthsADRs: 1.Mild BM depression 2. Loss of hair 3. Dose should be decreased in the presence of renal impairment

TerbinafineTerbinafineBelongs to a newer allylamine class of

antifungalsGiven both orally & locallyLipophillic so widely distributedFungicidal in contrast to azoles (fungistatic)Acts by non-competitive inhibition of “squalene

epoxidase” (early step enzyme in ergosterol synthesis (Image in Slide No. 22) – accumulation of squalene in fungal cells – cidal effect

Used for dermatophytes & candidaDose is 250mg OD for 2-6 wksLocally 1% ointment.

Terbinafine – contd.Terbinafine – contd.ADRsWith oral

◦ GIT upset◦ Hepatic dysfunction◦ Rash◦ Taste disturbance◦ No interaction with CYP450

Preparations and doses: ◦ 1% cream 125/250 mg tablets etc.◦ Tinea pedis: 250 mg OD for 2-6 weeks◦ Onychmycosis: 3-12 months (alternative to

fluconazole)

• On local application -On local application - ddryness, Erythemaryness, Erythema, , Rash, Rash, itching etc. itching etc.

Thank youThank you