Antifungal drugs
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Transcript of Antifungal drugs
Antifungal agents
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
• 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
Azoles inhibit
Polyenes (Disrupt membrane structure & function)
Flucytosine inhibits DNA synthesis
Caspofungin inhibits cell wall synthesis
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.
Classification based on structure
• ANTIBIOTICS
Polyene: Amphotericin, nystatin, hamycin
Hetrocyclic benzofuran: griseofulvin
• ANTIMETABOLITE : Flucytosine
• AZOLES
Imidazoles: Ketoconazole, clotrimazole,
oxiconazole,
miconazole,
Triazoles: Fluconazole, itraconazole,
voriconazole,
• ALLYLAMINES
– Terbinafine, butenafine
• ECHINOCANDINS
– Caspofungin, anidulafungin, micafungin
• OTHER TOPICAL AGENTS
– Tolnaftate, Undecyclinic acid, benzoic acid
Classification based on structure
Polyene antibiotics • Amphotericin B:
– Obtained from Streptomyces Nodosus– Amphoteric in nature
Lactone ring
Lipophilic part
Hydrophilic part
Mechanism of action
Mechanism of action Amphotericin B
Binds ergosterol in fungal cell membrane
Form pores in cell membrane
Cell contents leak out
Cell death
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.
Mechanism of resistance
• Resistance:– Replacement of ergosterol by other sterols in
fungal plasma membrane. – Resistance is not a problem clinically.
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
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
• 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
• 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
Disadvantages of AMB
Amphotericin B is toxic SIDE EFFECTS OF AMB
Nephrotoxicity
Acute infusion related reactions
Hypopotassemia, anemia, hepatic dysfunction..
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
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
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
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
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
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
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
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
• 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
• Adverse events: – Headache most common – GIT disturbances– CNS symptoms: confusion, fatigue, vertigo– Peripheral neuritis– Rashes, photoallergy– Transient leukopenia, albuminuria
• 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
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
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
Advantages of combination: – Entry of 5 FC– Reduced toxicity – Rapid culture conversion – Reduced duration of therapy – Decreased resistance
• 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
• 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
• 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
Ergosterol
14 α demethylase Ѳ Azoles
squalene 2,3 epoxide Ѳ
Lanosterol
Squalene Terbinafine
Mechanism of action:
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
Ketoconazole
– First orally effective broad spectrum antifungal – Effective against
• Dermatophytosis, Deep mycosis , Candidiasis
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
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
Drug Interactions
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
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
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
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
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
Itraconazole
Broadest spectrum of activity also against aspergillus
Fungistatic but effective in immunocompromised
Does not inhibit steroid hormone synthesis and no serious hepatoxicity
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
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
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
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
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
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
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
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
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
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
• 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
• 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
• 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
Systemic administration
Topical
Griseofulvin Ketoconazole
Ketoconazole Miconazole
Fluconazole Clotrimazole
Itraconazole Terbinafine
Terbinafine Nystatin
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
• Nystatin: Candidiasis only • Griseofulvin: Dermatophytosis only • Terbinafine : Dermatophytosis & candidiasis • Caspofungin: Aspergillosis & candidiasis
Spectrum of action
• 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