antifungaldrugs
TRANSCRIPT
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R.GAYATHRI DEVIPHARM D
Antifungal DrugsAntifungal Drugs
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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
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Opportunistic infectionsOpportunistic infectionsImmuno-suppression due to
- Cancer chemotherapy- AIDS◦Corticosteroid overuse
Indiscriminate use of broad spectrum antibiotics
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Fungal infectionsSuperficial
◦ Skin◦ Hair◦ Nails◦ Mucous
membrane
Deep◦ Tissues (muscle &
connective tissue)◦ Organs
Images of some superficial skin infectio
ns
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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
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MOST COMMON FUNGAL MOST COMMON FUNGAL PATHOGENSPATHOGENSDermatophytes – Microsporum,
Epidermophyton and Trichophyton
Candida – C. albicans, C. glabrata, C. tropicalis
AspergillusCryptococcusRhizopus
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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)
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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.
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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
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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
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Antifungal spectrumAntifungal spectrumMost Toxic antifungalFungicide at high and static at
low conc.Effective against
◦Candida albicans◦Histoplasma capsulatum◦Cryptococcus
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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
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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)
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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
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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)
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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)
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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
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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
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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
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Azole StructuresAzole Structures
Fluconazole Ketoconazole
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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)
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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
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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
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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
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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
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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
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Mechanisms of antifungal Mechanisms of antifungal resistanceresistance
Target enzyme modification
Ergosterol biosynthetic pathway
Efflux pumpsDrug import
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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
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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)
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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
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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
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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.
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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
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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
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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
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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
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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
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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
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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.
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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.
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