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ANTIFUNGAL

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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

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VIJA

y

TH