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1
ANTIFUNGAL
2
VIJA
y
Fungi are eukaryotes
Fungal infections Mycoses
Less frequent than bacterial & Virus but common.
Anyone can succumb to fungal infection but more at risk in older people, diabetics, pregnant women and burn wound.
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FUNGI MAY BE CLASSIFIED AS YEAST OR MOULDS.
Yeast like pathogenic Histoplasmosis
Coccidioidomycosis Blastomycosis Cryptococcosis Candida
Mould group of pathogenic Aspergillosis Dermatophytes Mucormicosis
Candida Spp. and Pneumocyst carinii are not pathogenic
pathogenic in immuno compromised patients
OPPORTUNISTIC INFECTION.
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Oropharyngeal Vaginal candidiasis Sporotrichosis (Granulomatus of skin & Lymph
abscess) Pityrosporum orbiculare - hyperpigmetnation
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Fungal infections classified as Superficial & Deep mycosis (Systemic)
Superficial affecting skin, hair, nails, mucous membranes.
Most common: Dermatophytoses Encouraged by hot (Hygiene)and humid
environment Dermatophytoses classified according to body site
• Tinea barbae • Tenia capitis(Scalp)• Tinea corporis(Body)• Tinea manuum(Hand)• Tinea pedis(Foot) • Tinea unguium(Nails)
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Systemic fungal infections: Affect deeper tissues and organs.
Systemic candidiasis (RTI)
Meningitis, endocarditis
Rhinocerebral mucormycosis (Thrombosis)
Pulmonary aspergillosis
Blastomycosis (lesion of skin) Histoplasmosis (cough , fever, multiple
pneumonic infiltrates)
Coccidioidomycosis
Pneumocystis carinii pneumonia
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Fungal cell structure and function is essential for understanding the pharmacology of antifungal agents.
Four targets in fungal pathogens:
Fungal Cell Wall
Fungal Cell Membrane
DNA/RNA Synthesis
Inhibition of fungal mitosis
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Fungal Cell Wall contain β- 1,3-D-glucan Depletion of glucan Leads to death Capsofungi
n
9Leading to cell death.
Altering membrane permeability
AMPHOTERICIN-B
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Ergosterol is the predominant sterol in many pathogenic fungi.
Squalene Terbinafine
squalene 2,3 epoxide Lanosterol Ergosterol
Azoles
14-demethylase
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Inhibits DNA synthesis by blocking the functions of a key enzyme in DNA replication- thymidylate synthetase.
Fungal cell mitosis by disrupting mitotic spindle formation-a critical step in cellular division.
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CLASSIFICATION BASED ON MECHANISM OF ACTION
Inhibitor of cell wall
synthesis: Caspofungin
Drugs altering membrane
permeability Amphotericin-B, Nystatin, Hamycin
Inhibit nucleic acid
Synthesis 5 Flucytosine
Disruption of mitotic
spindle Griseofulvin
Drugs altering membrane
synthesis Inhibition of ergosterol
Trimidazoles Fluconazle, Itraconazole, VoriconazoleImidazoles Ketoconazole, Miconazole, Clotrimazole.
Inhibition of ergosterol+ lanosterol Terbinafine
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Drugs altering membrane permeability Amphotericin-B Nystatin Hamycin
Amphotercin:
First drug introduced in 1950s
Obtained from Strepomyces nodosus
Systemic Antifungal drug
Polyene group- Multi lactone ring with conjugated double
bond .
One end – Hydroxyl group (OH)–polar (Hydrophilc)
Other end – Hydrocarbon group-non polar (Lipophilic)
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MOA:
Lipophilc end
Hydrophilc endCreates ion channel
Leading to cell death.
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PK:
Poor absorbed from GIT- effective against intestinal
fungal infection
For systemic - IV slow infusion
Peak antifungal activity at pH 6.0-7.5.
High con- Fungicidal, low- fungi static
90% plasma protein binding
T1/2- 15days ( binds with sterol)
It is insoluble in water colloidal suspension with
sodium desoxycholate(1:1)
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Antifungal spectrum & uses:
After advent of azoles groups, the use of AMB declined.
Still it is DOC for
Treatment of Invasive aspergillosis in immune compromised patients
Mucormycosis
Rapidly progressing histoplasmosis, blastomycosis, meningeal cocciodomycosis(intrathecal)
Topical use:- 3% cream for oropharngeal candidiasis,
Reserve drug for resistant case of KALA AZAR. Leishmania . Splenic enlargement
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Dose: 0.5 mg/kg/day Adverse events:
Acute reaction (infusion related events, chills, fever,
headache, nausea, vomiting)
Long term toxicity: nephrotoxicity(>4g), anemia (D.
Ery)
azotemia, hypokalemia
CNS toxicity : intrathecal administration-seizures,
headache, vomiting, nerve palsies
Hepatotoxicity rarely DI:-
Flucytosine –synergetic action inc. permeability FC Aminoglycoside inc. renal toxicity.
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3 new formulations available
AMB Lipid complex (ABLC): 35% AMB
incorporated in ribbon like particles of
dimyristoyl phospholipids
AMB colloidal dispersion (ABCD): Disc shaped
particles containing 50% each of AMB &
cholesteryl ester in aqueos dispersion
Liposomal AMB (Small Unilamellar Vesicles) :
10% AMB incorporated in SUV made up of
lecithin
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Special features of these formulations:
Milder acute reaction
Dec. infusion associated side effects
Can be used in intolerance to conventional preparations
Lower nephrotoxicity & anemia
Deliver AMB to reticular endothlial cell of liver spleen so useful in leshmania & immuno compromised
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Nystatin:
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 (1mg=2000U) Can be used in oral, cutaneous, conjunctival
candidiasis Adverse events: Gastrointestinal disturbances with
oral tablets
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Drugs altering membrane synthesisAzoles: 1970
Synthetic anti fungals
Broad spectrum
Fungistatic / Fungicidal
Most commonly used
Classified as imidazoles & triazoles Imidazoles: Two nitrogen in structure
Topical: Econazole, Miconazole, Clotrimazole Systemic : ketoconazole
Newer : Butaconazole, Oxiconazole, Sulconazole
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Triazoles : Three nitrogen in structure 1980
Fluconazole, itraconazole, voriconazole, Terconazole
Topical for superficial infections
Both these groups are
Structurally related compounds
Have same mechanism of action
Have similar antifungal spectrum
Acetyl CoA
Squalene
Lanosterol
(ergosterol)
AllylamineDrugs (Terbinafine)
Azoles
Squalene-2,3 oxide
Squalene monooxygenase
14-α-demethylase
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Miconazole & clotrimazole:
Topical use Cream, gel, spray, lotion ,solution , pessary
Dermatophyte infections ( pedis, cruris, corporis, versicolor)
Candida: oral pharyngeal, vaginal, cutaneous
Adverse events:
Local irritation , itching or burning
Miconazole shows higher incidence of vaginal irritation &
pelvic cramps
No systemic side effects
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Ketoconazole:
First orally effective broad spectrum antifungal Effective against
Dermatophytosis Deep mycosis Candidiasis
Pharmacokinetics: Effective orallyRequires acidic environment for absorption High protein binding Readily distributed, not to BBB Metabolized in liver, excreted in bile t1/2 = 8-10 hrs
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Dose : 200 mg OD or BD
Adverse events:
Nausea , vomiting , anorexia
Headache , paresthesia, alopecia
Reduces steroid, testosterone & estrogen synthesis
Thus can cause gynaecomastia,
oligospermia, loss of libido & impotence in males.
Menstrual irregularities & amenorrhoea in females
Elevation of liver enzymes
Hypersensitivity reaction like skin rashes
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Drug interactions: Inhibits CYP450 enzyme
H2 receptor blockers
↑ Sr conc of cisapride, terfenadine, astemizole, quinidine
Phenytoin toxicity
Sulfonylureas: hypoglycemia
Cyclosporine: nephrotoxicity
Warfarin: bleeding
Rifampicin, phenytoin ↑ metabolism of ketoconazole
Should not combine with AMB
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Use: Restricted use, most serious mycoses
Dermatophytosis: conc in stratum corneum
Monilial vaginitis : 5-7 days
Systemic mycosis: blastomycosis, histoplasmosis,
Coccidioidomycosis
Less efficacious than AMB & produces slower response
Efficacy low in immunocompromized and meningitis
Lower toxicity than AMB higher than triazoles
So triazoles have replaced it in systemic mycosis
High dose used in cushings syndrome
Topical: T.pedis, cruris, corporis, versicolor
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RESISTANCE
May develop by altered demethylase or
by enhanced removal from the fungal cell.
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Fluconazole:
Newer water soluble triazole
Oral, IV as well as topical
Broad spectrum antifungal activity
Candida, cryptococcosis, coccidioidomycosis
Dermatophytosis
Blastomycosis
Histoplasmosis
Sporotrichosis
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Pharmacokinetics:
94% oral bioavailability
Not affected by food or gastric pH
Primarily excreted unchanged in urine t1/2 = 25 -30 hrs
Poor protein binding (10-12%)
Widely distributed crosses BBB
T ½ -27-32hrs Adverse events:
GIT upset
Headache, alopecia, skin rashes, hepatic necrosis
Teratogenic effect
CYP450 Enzyme inhibiting property less
No anti androgenic & other endocrine effects
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Drug Interactions:
Effects hepatic drug metabolism to lesser extent than
Ketoconazole
H2 blockers & PPI do not effect its absorption
Uses:
Candida:
150 mg oral dose cure vaginal candidiasis with few relapse
Oral candidiasis 2 weeks treatment required
Tinea infections & cutaneous candidiasis:
150 mg weekly 4 weeks, tinea unguim 12 months
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Disseminated candidiasis, cryptococcal,
coccidiodal meningitis & other systemic fungal
infections:
200-400 mg / day 4- 12 weeks or longer
3 days oral Candida UTI (100-800mg OD)
Meningitis preferred drug
Eye drops for fungal keratitis
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Itraconazole:
Broadest spectrum of activity also against aspergillus
Fungistatic
Pharmacokinetics:
50-60% bioavailability, absorption is variable,
enhanced by food & gastric acidity
High protein binding 99 %
Well distributed accumulates in vaginal mucosa, skin,
nails but CNS penetration is poor
Metabolized in liver CYP3A4 excreted in feces t1/2=
30- 64hr
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Adverse events:
GI Intolerance
Dizziness, pruritis , headache, hypokalemia, hypotension
Increase plasma transaminase
Rarely Hepatotoxicity
Drug interactions:
Oral absorption decreased by antacids, H2 blockers
Rifampicin, phenytoin induce metabolism
Potentiates effect of hypnotic drugs
Inhibits CYP3A4 drug interaction profile similar to
ketoconazole
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Uses:
DOC for paracoccidomycosis & chromoblastomycosis
DOC for histoplasmosis & blastomycosis in AIDS patients
Esophageal, oropharyngeal vaginal candidiasis
Not superior to fluconazole : 200 mg OD X 3 days
Dermatophytosis: less effective than fluconazole
100- 200 mg OD X 15 days
Onychomycosis : 200 mg / day for 3 months
Intermittent pulse regime 200 BD once weekly for 3 months
equally effective
Aspergillosis: 200 mg OD/ BD with meals for 3 months or
more
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Voriconazole:
II generation triazole
High oral bioavailability, low protein binding
Good CSF penetration
Metabolized by CYP2C19
Doesn’t require gastric acidity for absorption
T1/2-6 hrs Uses:
DOC for invasive aspergillosis
Most useful for esophageal candidiasis
First line for moulds like fusarium
Useful in resistant candidal infections
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Dose : 200 mg BD Adverse events:
Transient visual changes like blurred vision , altered
color perception & photophobia
Rashes in 5 -6 %
Elevated hepatic enzymes
Prolongation of QT
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Cell wall synthesis inhibitor: Capsofungin
Introduced in 2000s.
Echinocandins
MOA: Inhibits- β-(1,3)-D-glucan
T½-9-11hrs.
P.B- albumin 97%
Excreted through urine(41%) and feces (35%)
Dose: IV infusion (intial 70mg slowly then
50mg/day) »Contd.,
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Active against wide variety of fungi.
Effective treatment for Aspergillus infection
and Candidiasis (Esophageal, intra abdominal
peritontis).
ADR: Sensation of warmth, flushing, rashes.
DI:- Cyclosporine hepatotoxicity.
5 Flucytosine Prodrug, pyrimidine analogue, anti metabolite
Mechanism of action Converted to 5 FU by FUNGAL CYTOSINE DEAMINASE 5FU 5FUTP RNA DEFECTIVE 5FU 5dUMP Inhibit Thymidylate synthesis
,
Human cells cant convert it to 5FU Adverse events:
Bone marrow toxicity , GIT , Alopecia, skin rashes, itching , rarely hepatitis
5-flucytosine (outside)
permease5-flucytosine (inside)
Cytosine deaminase
5-fluorouracil
5-FUMPRNA
Phosphoribosyltransferase
5dUMP(inhibits thymidylatesynthase)
Uses: in combination with AMB in cryptococcal meningitis
,
Advantages of combination: Entry of 5 FC Reduced toxicity Rapid culture conversion Reduced duration of therapy & resistance
SYSTEMIC ALLY FOR TOPICAL INFECTIONS
Terbinafine: Orally & topically effective drug against candida
& dermatophytes Fungicidal : shorter courses of therapy required
& low relapse rates Mechanism of action: Inhibition of Lanosterol + Ergosterol
production Pharmacokinetics:
Well absorbed orally 75% Highly keratophilic & lipophilic High protein bound , poor BBB permeability Metabolized in liver excreted in urine & feces
t1/2- 15 days Negligible effect on CYP450
Adverse events: Nausea , vomiting , Diarrhoea Taste disturbancesRarely hepatic dysfunction Topical: erythema , itching , dryness ,
urticaria, rashes Uses:
Dermatophytosis: topically/ orally 2- 6 weeks
Onychomycosis: first line drug 3- 12 months
Candidiasis: less effective 2- 4 weeks therapy may be used as alternative 250 mg OD
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Griseofulvin :-
Fungistatic
Obtained from Pencillium griseofulvum
Systemic administration for topical infections
Fatty meal inc. BV
T1/2- 24hrs
Drug binds to keratin in stratum corneum of the
skin
Mechanism of action:-
Interact with polymerised microtubles causing disruptions of mitotic spindle and arrest mitosis metaphase
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Uses:-
Dematophytosis caused by Microsporum
Trichophyton, Epidermatophyton
Duration of therapy depend open the body
area
TINEA CORPORIS – 2-4 WEEKS
TINEA CAPITIS -4-6WEEKS
TINEA PEDIS – 4-8 WEEKS
Dose- 500-1000mg/day/in 2doses
OTHER DRUGS Ciclopirox olamine - may block amino acid transport -
penetrates well - useful for Candida and dermatophytes
Haloprogin - useful for dermatophytes and Candida, may cause burning
Tolnaftate - useful for dermatophytes - inhibits synthesis of macromolecules
Undecylenic acid - dermatophytes
KI - taken orally for cutaneous sporotrichosis - may cause a rash and irritation of salivary and lacrimal glands
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Disease 1st choice drugs 2nd choice drugs
Candiasis oral/vaginal/cutaneous disseminated
FLU/NYS/CLOAMB/VOR
ITRFLU
Cryptococcosis AMB+/- 5-FC FLU
Histoplasmosis ITR/AMB FLU
Coccidioidomycosis AMB/FLU ITR/KTZ
Blastomycosis ITR/AMB KTZ/FLU
Sporotrichosis AMB ITR
Paracoccidioidomycosis
ITR AMB
Aspergillosis AMB/VORI ITR
Mucormycosis AMB -
Chromomycosis ITR KTZ/5-FC
VIJAY
VIJA
y
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Systemic administration
Topical
Griseofulvin Ketoconazole Ketoconazole Miconazole Fluconazole Clotrimazole Itraconazole Terbinafine Terbinafine Nystatin
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SPECTRUM OF ACTION
AMB 5FC KTZ FLU ITR
Aspergillus -- -- -- Y
Blastomycosis
-- Y Y Y
cryptococcus
Y -- Y Y
Coccidiodo -- Y Y Y
candida Y Y Y Y
Histoplasma -- Y Y Y
Mucor -- -- -- --
Sporotrichosis
-- -- Y Y
chromoblast
dermatophyte
Fusarium
TOPICAL AZOLESClotrimazoleMiconazoleEconazoleOxiconazoleSertaconazole
TerconazoleSulconazoleTioconazoleButoconazole
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Nystatin: Candidiasis only
Griseofulvin: Dermatophytosis only
Terbinafine : Dermatophytosis & candidiasis
Caspofungin: Aspergillosis & candidiasis
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Some important characteristics:
Broad spectrum: AMB, KTZ, FLU, ITR
Resistance: 5 FC
Nephrotoxic/ Anemia: AMB
LEUCOPENIA: 5 FC
GIT upset: All
Over all toxicity: highest for AMB lowest for
fluconazole, itraconazole
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VIJA
y
For SYSTEMIC
Grisofulvin K M C F I T Nystatin
For Topical
57
VIJA
y
TH