Download - Antifungal drugs
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Antifungal agents
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Yeasts
• Fungi may be classified as
Moulds
• Yeasts: Blastomyces, candida, histoplasma, coccidioides,
cryptococcus.
• Moulds: Aspergillus spp. Dermatophytes, mucor
Superficial mycosis
• Clinically classified as:
Deep (systemic) mycosis
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• Systemic fungal infections: – Systemic candidiasis: RTI with progressive
dimunition – Cryptococcal meningitis, endocarditis– Rhinocerebral mucormycosis – Pulmonary aspergillosis– Blastomycosis (pneumonitis, with dissemination)– Histoplasmosis(cough , fever, multiple pneumonic
infiltrates)– Coccidiodomycosis– Pnemocystis carinii pneumonia
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Azoles inhibit
Polyenes (Disrupt membrane structure & function)
Flucytosine inhibits DNA synthesis
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Caspofungin inhibits cell wall synthesis
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Classification based on mechanism of action
1. Fungal cell wall synthesis inhibition: Caspofungin.
2. Bind to fungal cell membrane ergosterol: Amphotercin–B, Nystatin.
3. Inhibition of ergosterol + lanosterol synthesis: Terbinafine, Naftifine, Butenafine.
4. Inhibition of ergosterol synthesis: Azoles
5. Inhibition of nucleic acid synthesis: 5–Flucytosine.
6. Disruption of mitotic spindle and inhibition of fungal mitosis: Griseofulvin.
7. Miscellaneous: • Ciclopirox, Tolnaftate, Haloprogin, Undecylenic acid, Topical
azoles.
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Classification based on structure
• ANTIBIOTICS
Polyene: Amphotericin, nystatin, hamycin
Hetrocyclic benzofuran: griseofulvin
• ANTIMETABOLITE : Flucytosine
• AZOLES
Imidazoles: Ketoconazole, clotrimazole,
oxiconazole,
miconazole,
Triazoles: Fluconazole, itraconazole,
voriconazole,
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• ALLYLAMINES
– Terbinafine, butenafine
• ECHINOCANDINS
– Caspofungin, anidulafungin, micafungin
• OTHER TOPICAL AGENTS
– Tolnaftate, Undecyclinic acid, benzoic acid
Classification based on structure
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Polyene antibiotics • Amphotericin B:
– Obtained from Streptomyces Nodosus– Amphoteric in nature
Lactone ring
Lipophilic part
Hydrophilic part
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Mechanism of action
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Mechanism of action Amphotericin B
Binds ergosterol in fungal cell membrane
Form pores in cell membrane
Cell contents leak out
Cell death
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Antifungal spectrum
- Aspergillus- Blastomyces dermatitidis- Candida albicans - Cryptococcus neoformans- Coccidioides immitis- Histoplasma capsulatum- Mucor spp.Also active against Leshmania
Broadest spectrum of action
Fungicidal at high & static at low conc.
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Mechanism of resistance
• Resistance:– Replacement of ergosterol by other sterols in
fungal plasma membrane. – Resistance is not a problem clinically.
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Pharmacokinetics
• Poorly absorbed orally • Insoluble in water so colloidal
suspension prepared with sodium deoxycholate(1:1 complex)
• 90% bound to plasma proteins • Metabolized in liver slowly
excreted in urine • t ½ = 15 days
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Administration & dose
• Systemic mycosis: IV – Available as 50mg vial – suspended in 10 ml water
and then diluted with 500 ml glucose – 0.5mg/kg to 1 mg/kg– Total dose- 3-4 gm over 2-3 months
• Intestinal Monoliasis: 50-100 mg QID Orally• Vaginitis: topical • Otomycosis: 3 % drops • Intrathecal: 0.5 mg BD in fungal meningitis
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• Useful drug in nearly all life threatening mycotic infections
• Treatment of invasive aspergillosis • Rapidly progressive Blastomycosis &
Coccidiomycosis• Cryptococcus neoformans• Mucormycosis.• Disseminated rapidly progressing Histoplasmosis • Reserve drugs for resistant kala azar • Topical uses:
Uses
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• Adverse events: – Acute reaction:
– Chills, fever, headache, pain all over, nausea, vomiting, dyspnoea lasting 2-5 hrs because of release of IL & TNF
– can be treated with hydrocortisone 0.6mg/kg
– Long term toxicity: – Nephrotoxicity: Azotemia,
Hypokalemia, acidosis, ↓ GFR – anemia
– CNS toxicity : intrathecal administration, headache, vomiting, nerve palsies
– Hepatotoxicity rarely
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Disadvantages of AMB
Amphotericin B is toxic SIDE EFFECTS OF AMB
Nephrotoxicity
Acute infusion related reactions
Hypopotassemia, anemia, hepatic dysfunction..
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Lıpıd formulations of amphotericin B
(ABLC; Abelcet®)
(ABCD; Amphocil® or Amphotec®)
(L-AMB; Ambisome®)
Amphotericin B Lipid Complex
Amphotericin B Colloidal Dispersion
Liposomal Amphotericin B
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ABLC
Ribbon-like particles
Carrier lipids: DMPC, DMPG
J Liposome Res 1993; 3: 451
AMB Lipid complex (ABLC):
35% AMB incorporated in ribbon like particles of dimyristoyl phospholipids
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ABCD
Disk-shaped particles
Carrier lipid: Cholesteryl sulfate
J Pharmaceutics 1991; 75: 45
AMB colloidal dispersion (ABCD):
Disc shaped particles containing 50% each of AMB & cholesteryl ester in aqueos dispersion
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The ‘LIPOSOME’..
Hospital Practice 1992; 30: 53
• Liposomal AMB (Small unilamellar vesicles) :
10% AMB incorporated in SUV made up of lecithin
Lipid formulations:20-50 times more expensive than AmB-deoxycholate
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Milder acute reaction Can be used in intolerance
to conventional preparationsLower nephrotoxicity &
anemiaDeliver AMB to RES of liver
speen so useful in leshmania & immunocompromised
Can be used in higher
doses
Major advantages of lipid AMB formulations
Liposomes in the therapy of infectious diseases and cancer 1989: 105
Release frommacrophage
MacrophageMacrophage
Release in bloodcompartment
Endocytosis
Liposome LysosomeFusion
Liposomedegradation
Endocyticvesicle
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NystatinObtained from S.NourseiSimilar 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 TDS1 lac U in vaginitis Prevention of oral candidiasisCan be used in oral, cutaneous, conjunctival candidiasis
Adverse events: Gastointestinal disturbances with oral tablets
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Hamycin:S. PimprinaHindustan antibiotics pimpri More water soluble, fraction absorbed orally but unreliable
in systemic infectionsTopical use in thrush, cutaneous candidiasis, trichomonas
& monilial vaginitis, otomycosis by aspergillusNatamycin:
Similar to nystatin, broad spectrum Used topically 1%, 3% ointmentFusarium solani keratitis, trichomonas & monilial vaginitis
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Griseofulvin• One of early antibiotics from penicillium
griseofulvum• Fungistatic, systemic drug for superficial fungal
infections• Active against most dermatophytes• Dermatophytes concentrate it actively hence
selective toxicity • Resistance: loss of concentrating ability
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• Mechanism of action: – Griseofulvin interacts with
polymerized microtubules and disrupts the mitotic spindles thus arresting fungal mitosis
• Pharmacokinetics: – Oral administration, irregular
absorption, increased by fatty food and microfine particles
– Gets conc in keratinized tissue– Metabolized in liver, excreted in
urine,t1/2=24 hrs
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• Adverse events: – Headache most common – GIT disturbances– CNS symptoms: confusion, fatigue, vertigo– Peripheral neuritis– Rashes, photoallergy– Transient leukopenia, albuminuria
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• Uses: – Systemically only for dermatophytosis, ineffective
topically • Systemic azoles more effective and preferred • Duration of treatment depends on site,
thickness of keratin and turnover of keratin. • Treatment must be continued till infected
tissue is completely replaced by normal skin,hair, nail.
• Dose: 125-250 mg QID
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Duration of treatment
• Body skin = 3 weeks• Palm, soles = 4- 6 weeks• Finger nails = 4- 6months• Toe nails = 8 – 12 months• Griseofulvin should be reserved for nail hair or
larger body surface involvement • Interactions:
– Warfarin , OCP– Phenobarbitone, Disulfiram like reaction
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5 flucytosine
– Prodrug, pyrimidine analog, antimetabolite – Converted to 5 FU – Human cells cant convert it to 5FU – Adverse events:
• Bone marrow toxicity , GIT , Alopecia, skin rashes, itching , rarely hepatitis
– Uses: in combination with AMB in cryptococcal meningitis
– Narrow spectrum of action
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Advantages of combination: – Entry of 5 FC– Reduced toxicity – Rapid culture conversion – Reduced duration of therapy – Decreased resistance
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• Differences between AMB & 5 FC • AMB = Active drug, broad spectrum, antibiotic,
fungicidal • Not absorbed, high protein binding, no BBB,
metabolized in liver, highly efficacious, IV,Intrathecal,topical
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• Azoles: – Synthetic antifungals– Broad spectrum – Fungistatic or fungicidal depending on conc of
drug – 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 – Fluconazole, itraconazole, voriconazole– Terconazole: Topical for superficial infections
• Both these groups are – Structurally related compounds– Have same mechanism of action – Have similar antifungal spectrum
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Ergosterol
14 α demethylase Ѳ Azoles
squalene 2,3 epoxide Ѳ
Lanosterol
Squalene Terbinafine
Mechanism of action:
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Miconazole & clotrimazole
• Topical use: – Miconazole 2 % and clotrimazole 1 % applied BD for
2 weeks in pityriasis versicolor, 4 weeks in cruris, capitis and corporis
• Uses: – Dermatophyte infections– Candida: oral pharyngeal, vaginal, cutaneous
• Adverse events: – Local irritation , itching or burning – Miconazole shows higher incidence of vaginal irritation &
pelvic cramps
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Ketoconazole
– First orally effective broad spectrum antifungal – Effective against
• Dermatophytosis, Deep mycosis , Candidiasis
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Pharmacokinetics• Effective orally• acidic environment
favours absorption • High protein binding • Readily distributed, not to
BBB • Metabolized in liver,
excreted in bile• t1/2 = 8- 10 hrs • Dose : 200 mg OD or BD
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Adverse events• Nausea , vomiting , anorexia • Headache , paresthesia, alopecia• ↓ steroid, testosterone & estrogen synthesis
– Gynaecomastia, oligospermia , loss of libido & impotence in males
– Menstrual irregularities & amenorrhoea in females
• Elevation of liver enzymes • Hypersensitivity reaction - skin rashes, itching
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Drug Interactions
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Uses
• Dermatophytosis: conc in stratum corneum • Monilial vaginitis : 5-7 days • Systemic mycosis: blastomycosis,
histoplasmosis, coccidiodomycosis – Less efficacy than AMB & slower response– ↓Efficacy in immunocompromized and meningitis– Lower toxicity than AMB higher than triazoles
• High dose used in cushings syndrome• Topical: T.pedis, cruris, corporis, versicolor
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Fluconazole
• Newer water soluble triazole – Oral, IV as well as topical – Broad spectrum antifungal activity
• Candida, cryptococcosis, coccidiodomycosis • Dermatophytosis• Blastomycosis • Histoplasmosis • Sporotrichosis • Not effective against aspergillosis & mucormycosis
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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 Widely distributed crosses BBB
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Adverse events
GIT upset Headache, alopecia, skin rashes, hepatic necrosis Teratogenic effect CYP450 Enzyme inhibiting property less Interactions:
Effects hepatic drug metabolism to lesser extent than Ketoconazole
H2 blockers & PPI do not effect its absorption No anti androgenic & other endocrine effects
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UsesCandida:
150 mg oral dose can cure vaginal candidiasis with few relapse
Oral candidiasis- 2 weeks treatment required Tinea infections & cutaneous candidiasis: 150 mg
weekly for 4 weeks, tinea unguim : 12 months systemic fungal infections: Disseminated
candidiasis, cryptococcal, coccidiodal meningitis 200-400 mg / day 4- 12 weeks or longer
Meningitis: preferred drug Eye drops for fungal keratitis
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Itraconazole
Broadest spectrum of activity also against aspergillus
Fungistatic but effective in immunocompromised
Does not inhibit steroid hormone synthesis and no serious hepatoxicity
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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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Uses
DOC for paracoccidomycosis & chromoblastomycosis DOC for histoplasmosis & blastomycosis 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 a week / month for 3 months equally effective
Aspergillosis: 200 mg OD/ BD with meals for 3 months or more
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Adverse events
• GI Intolerance• Dizziness, pruritis , headache , hypokalemia • Increase plasma transaminase• Rarely hepatotoxicity • Drug interactions:
– Oral absorption ↓by antacids, H2 blockers – Rifampicin, phenytoin induce metabolism – Inhibits CYP3A4 drug interaction profile similar to
ketoconazole
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Triazoles
Itraconazole- Varied absorption.
Metabolized by cyt P450
- less endocrine effects but occur at high doses
- Less penetration in CSF - Many drug interactions
(due to inhibition of CYT P450/ 3A4)
Fluconazole- Completely absorbed and
better tolerated, Renal excretion
- Less endocrine effects - Penetrates well into CSF- Drug Interactions
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VoriconazoleII 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 candida infections
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Dose and Adverse effects
• 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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TerbinafineOrally & topically effective drug against candida
& dermatophytes Fungicidal : shorter courses of therapy required
& low relapse rates Mechanism of action: Pharmacokinetics:
Well absorbed orally 75%Highly keratophilic & lipophilic High protein bound , poor BBB permeability t1/2- 15 daysNegligible effect on CYP450
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Adverse events and uses
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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Caspofungin acetate
Semisynthetic antifungalMOA: Inhibits B (1,3) D glucan an essential
component of fungal cell wall Uses: Treatment of invasive aspergillosis &
candidiasis (esophageal, intraperitoneal) Dose: IV 70 mg slowly then 50 mg daily
infusion Adverse events:
Flushing rashes , nausea, vomiting, phlebitis
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Topical agents used in dermatophytosis
Tolnaftate: Tinea, cruris, corporis, 1- 3 weeks treatment Not effective in hyperkeratinized lesions Salicylic acid aids its effect by keratolysis
Ciclopirox olamine: Tinea infections, pitryasis versicolor ,dermal
candidiasis, vaginal candidiasis Penetrates superficial layers Acts by inhibiting membrane uptake of precursors
of macromolecules needed for fungal growth
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• Undecyclenic acid: 5% (Tineafax) – Generally combined with zinc (20%) – Requires prolonged treatment has high relapse
rate – Weaker antifungal action used in tinea cruris and
nappy rash• Sodium thiosulfate: (Karpin lotion)
– Reducing agent known as hypo – Effective in pitryasis versicolor only 20 % solution
for 3-4 weeks
Topical agents used in dermatophytosis
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• Benzoic acid: – Used in combination with salicylic acid – Whitfields ointment: ( benzoic acid 6% + salicyclic
acid 3 %)– Salicyclic acid due to its keratolytic action helps to
remove infected tissue & promotes penetration of benzoic acid in fungal infected lesion
– Adverse events: irritation & burning sensation (Ring cutter ointment)
Topical agents used in dermatophytosis
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• Quinidiochlor; – Luminal amoebicide – Weak antifungal & antibacterial – External application : dermatophytosis , mycosis
barbae, pitryasis versicolor • Selenium sulfide: T versicolor • Potassium iodide: Dermatophytic infection
Topical agents used in dermatophytosis
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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
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• Nystatin: Candidiasis only • Griseofulvin: Dermatophytosis only • Terbinafine : Dermatophytosis & candidiasis • Caspofungin: Aspergillosis & candidiasis
Spectrum of action
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• 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
Important characteristics