Mansi Patel

ANTIFUNGAL DRUGS PRESENTED BY :MANSI BHALODIYA SEM – VI (B. PHARM) L. M. COLLEGE OF PHARMACY Content ● ● ● ● ● ● Introduction Cell structure and function Difference between fungi and bacteria Types of fungal infections Antifungals Classification Introduction to Fungi ► The word fungus comes from the Latin word for mushrooms ► The kingdom Fungi includes an enormous variety of living organisms collectively referred to as Ascomycota, or true Fungi ► Fungi are not capable of photosynthesis: they are heterotrophic because they use complex organic compounds as sources of energy and carbon Introduction to Fungi (Contd.) ► Like bacteria, fungi play an essential role in ecosystems because they are decomposers and participate in the cycling of nutrients by breaking down organic and inorganic materials to simple molecules ► Fungi often interact with other organisms, forming beneficial or mutualistic associations ► In humans, fungal infections are generally considered challenging to treat. Unlike bacteria, fungi do not respond to traditional antibiotic therapy because they are eukaryotes ► Fungi have many commercial applications. The food industry uses yeasts in baking, brewing, and cheese and wine making. Many industrial compounds are byproducts of fungal fermentation. Fungi are the source of many commercial enzymes and antibiotics Pathogenic fungus ► ► Pathogenic fungi are fungi that cause disease in humans or other organisms. Approximately 300 fungi are known to be pathogenic to humans ► Most common ones:► Candida ► Aspergillus ► Cryptococcus ► Histoplasma ► Pneumocystis ► Stachybotrys Fungi Cell Structure and Function ► Fungi are unicellular or multicellular thick-cell-walled heterotroph decomposers that eat decaying matter . ► Fungi are eukaryotes and have a complex cellular organization. As eukaryotes, fungal cells contain a membrane-bound nucleus where the DNA is wrapped around histone proteins ► Fungal cells also contain mitochondria and a complex system of internal membranes, including the endoplasmic reticulum and Golgi apparatus ► The rigid layers of fungal cell walls contain complex polysaccharides called chitin and glucans. Chitin gives structural strength to the cell walls of fungi ► Fungi have plasma membranes similar to other eukaryotes, except that the structure is stabilized by ergosterol: a steroid molecule that replaces the cholesterol found in animal cell membranes Fungal Cell Fungal Cell Wall Difference between Bacteria and Fungi Bacteria Fungi ► Prokaryotic (without true nucleus) organisms ► Eukaryotic (with true nucleus) organisms ► Most bacteria grow best around neutral pH values (6.5 - 7.0) ► Most fungi grow best around slightly acidic pH (4-6) ► Bacteria are unicellular organisms that are visible only under microscope ► Fungi are unicellular (Yeast) or multi-cellular filamentous organisms ► Bacterial cell is without true nucleus and membrane bound organelles ► Fungal cell is with true nucleus and membrane bound organelles ► Cell wall is made up of peptidoglycan ► Fungal cell wall is made up of chitin ► Sterols are absent in cell membrane ► Sterols are present in cell ► Bacteria reproduce by binary fission ► Reproduce by sexual and asexual spores ► Bacteria are sensitive to antibiotics but resistant to Griseofulvin ► Fungi are resistant to antibiotics like Penicillin, Chloramphenicol etc but sensitive to Griseofulvin Types of fungal infections ► ASPERGILLOSIS: Caused by the fungus Aspergillus and usually occurs in people with lung diseases or weakened immune systems. ► CANDIDIASIS: Caused by the yeast Candida. Candidiasis can occur in the mouth and throat, vagina, or the bloodstream. ► FUNGAL NAIL INFECTIONS: Common infections of the fingernails or toenails. ► MUCORMYCOSIS: A rare infection that mainly affects people with weakened immune systems. ► PNEUMOCYSTIS PNEUMONIA (PCP): Caused by the fungus Pneumocystis jirovecii and mainly affects people with weakened immune systems. Types of fungal infections (Contd.) ► C. NEOFORMANS INFECTION: Caused by Cryptococcus neoformans, which can infect the brain, causing meningitis in people with weakened immune systems, particularly those who have HIV/AIDS. ► FUNGAL EYE INFECTIONS: Rare infections that can develop after an eye injury or eye surgery. ► RINGWORMA: common fungal skin infection that often looks like a circular rash. Antifungals ► An antifungal medication, also known as an antimycotic medication, is a pharmaceutical fungicide or fungistatic ► It is used to treat and prevent mycosis such as athlete’s foot, ringworm, candidiasis (thrush), serious systemic infections such as cryptococcalmeningitis, and others. Classfication of antifungals based on M/A ► Fungal cell wall synthesis inhibition: Echinocandins- caspofungin, micafungin ► Bind to fungal cell membrane ergosterol: Polyenes ► Inhibition of ergosterol + lanosterol synthesis: Allylamines ► Inhibition of ergosterol synthesis: Azoles ► Inhibition of nucleic acid synthesis: Pyrimindines- 5FC ► Disruption of mitotic spindle and inhibition of fungal mitosis: Griseofulvin Mechanism of Action of Antifungals Echinocandin • CASPOFUNGIN • ANIDULAFUNGIN Caspofungin ► Caspofungin acetate is an parenteral injection used in the treatment of invasive aspergillosis in patients refractory to or intolerant of other antifungal therapies ► Studies have shown caspofungin to be effective against invasive candidiasis ► It is a semisynthetic lipopeptide (echinocandin) derived from a fermentation product of Glarea lozoyensis Caspofungin (contd.) ► Mechanism of Action: Caspofungin is a (1,3)-D-glucan synthesis inhibitor, thus disrupting the formation of β-glucan in the cell walls. β-glucan is essential to the structural integrity of the cell wall ► Adverse effects: thrombophlebitis, vein irritation, histamine-related symptoms etc. Anidulafungin ► Used to treat infections by Candida ► Mechanism of Action: It inhibits glucan synthase, disrupting the formation of b-glucan. It is especially effective against fluconazole-resistant Candida ► Adverse Effects: Diarrhea, elevation of liver enzymes. Chemical classification of Antifungals Antibiotics ► Polyenes: Amphotericin B (AMB), Nystatin, Hamycin ► Echinocandins: Caspofungin, Micafungin, Anidulafungin ► Heterocyclic benzofuran: Griseofulvin Antimetabolite ► Flucytosine (5-FC) ► Imidazoles Topical: Clotrimazole, Econazole, Miconazole, Azoles Allylamine Other topical agents Oxiconazole ► Imidazoles Systemic: Ketoconazole ► Triazoles (systemic): Fluconazole, Itraconazole, Voriconazole, Posaconazole ► Terbinafine ► Tolnaftate, Undecylenic acid, Benzoic acid, ► Quiniodochlor, Ciclopirox olamine, Butenafine, ► Sod. thiosulfate ANTIBIOTICS • AMPHOTERICIN B (AMB) • NYSTATIN • HAMYCIN • NATAMYCIN • GRISEOFULVIN Polyene Antibiotics Amphotericin B (AMB) ► Obtained from Streptomyces nodosus ► Amphoteric in nature ► The polyenes possess a macrocyclic ring, one side of which has several conjugated double bonds and is highly lipophilic, while the other side is hydrophilic with many OH groups Hydrophilic side Lipophilic side AMB (Mechanism of action) ► Amphotericin B binds with ergosterol, a component of fungal cell membranes, forming pores that cause rapid leakage of monovalent ions (K+, Na+, H+ and Cl−) and subsequent fungal cell death. This is amphotericin B's primary effect as an antifungal agent. AMB (Pharmacokinetics) ► Poorly absorbed orally ► Insoluble in water so colloidal suspension Prepared with sodium deoxycholate (1:1Complex) ► 90% bound two plasma proteins ► Metabolized in liver slowly excreted in urine ► t ½ =15 days AMB (Interactions) ► Flucytosine: Toxicity of flucytosine is increased and allows a lower dose of amphotericin B. Amphotericin B may also facilitate entry of flucystosine into the fungal cell by interfering with the permeability of the fungal cell membrane ► Diuretics or cisplatin: Increased renal toxicity and increased risk of hypokalemia ► Corticosteroids: Increased risk of hypokalemia ► Cytostatic drugs: Increased risk of kidney damage, hypotension, and bronchospasms AMB Uses ► Amphotericin B is used to treat serious, life-threatening fungal infections. It is not for use in treating a minor fungal infection such as a yeast infection of the mouth, esophagus, or vagina. Amphotericin is usually given after other antifungal antibiotics have been tried without successful treatment of symptoms. ► Used in nearly all life threatening mycotic infections ► Treatment of invasive aspergillosis ► Rapidly progressive Blastomycosis and coccidiomycosis ► Cryptococcus neoformans ► Mucormycosis ► Disseminated rapidly progressing Histoplasmosis ► Reserve drugs for resistant kala azar ► Topical uses AMB (Side effects) ► injection site reactions (pain, swelling, irritation), ► fever, ► shaking, ► chills, ► flushing, ► loss of appetite, ► weight loss, ► dizziness, ► nausea, ► vomiting ► diarrhea, ► upset stomach, ► headache, ► shortness of breath, ► muscle or joint aches, ► warmth/redness/tingly feeling under your skin, ► itching or rash, or ► fast breathing 1 to 3 hours after the infusion starts. Nystatin ► Obtained from S.Noursei ► 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: ► ► intestinal moniliasis ,vaginitiss ► Prevention of oral candidiasis ► Can be used in oral, cutaneous, conjunctival candidiasis Adverse events: ► Gastointestinal disturbances with oral tablets Hamycin ► Hamycin is obtained from a strain of streptomyces bacteria growing in soil i.e., Streptomyces pimprin ► It is similar to nystatin ► More water soluble, fraction absorbed orally but unreliable in systemic infections ► Topical use in thrush, cutaneous candidiasis, trichomonas & monilial vaginitis, otomycosis by aspergillus ► Used in systemic mycoses Natamycin ► It is also known as pimaricin. ► Similar to nystatin, broad spectrum ► Used topically 1%, 3% ointment mostly to treat fungal infections around the eye 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 Griseofulvin (Adverse events and Uses) ► 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 Griseofulvin (Contd.) ► 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 ANTIMETABOLITE • FLUCYTOSINE (5-FC) 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 5 flucytosine (Mechanism of Action) ► Flucytosine is intrafungally converted into the cytostatic fluorouracil which undergoes further steps of activation and finally interacts as 5fluorouridinetriphosphate with RNA biosynthesis thus disturbing the building of certain essential proteins ► Flucytosine also undergoes conversion into 5fluorodeoxyuridinemonophosphate which inhibits fungal DNA synthesis • AZOLES • IMIDAZOLES • Miconazole & clotrimazole • Ketoconazole TRIAZOLES • Fluconazole • Itraconazole • Voriconazole 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 Mechanism of Action Miconazole & clotrimazole ► Topical use: Miconazole 2 % and clotrimazole 1 % ► 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 ► Metabolized in liver, excreted in bile ► t1/2 = 8- 10 hrs • Dose : 200 mg OD or BD Ketoconazole (Adverse Events) ► Nausea , vomiting , anorexia ► Headache ► ↓ 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 Ketoconazole (Uses) ► Dermatophytosis ► Monilial vaginitis : 5-7 days ► Systemic mycosis: ► Blastomycosis etc ► Less efficacy than AMB & slower response ► Lower Efficacy in immunocompromized and meningitis ► Lower toxicity than AMB higher than triazoles ► High dose used in cushings syndrome ► Used topically Triazoles ► Three nitrogen in structure ► Fluconazole, itraconazole, voriconazole ► Terconazole: Topical for superficial infections 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 Fluconazole (Contd.) ► ► 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, skin rashes etc ► CYP450 Enzyme inhibiting property less Interactions 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 Itraconazole (Uses) ► DOC for paracoccidomycosis & chromoblastomycosis ► DOC for histoplasmosis & blastomycosis ► Esophageal, oropharyngeal vaginal candidiasis, Not superior to fluconazole ► Dermatophytosis: less effective than fluconazole ► Onychomycosis : 200 mg / day for 3 months ► Aspergillosis: 200 mg OD/ BD with meals for 3 months or more Itraconazole (Adverse events) ► GI Intolerance ► Dizziness, headache etc ► Increase plasma transaminase ► Drug interactions: ► Oral absorption ↓by antacids, H2 blockers ► Rifampicin, phenytoin induce metabolism ► Inhibits CYP3A4 drug interaction profile similar to ketoconazole 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 candida infections Voriconazole (Adverse events) ► ► ► Transient visual changes like blurred vision , altered color perception & photophobia Rashes in 5 -6 % Elevated hepatic enzymes ALLYLAMINE • TERBINAFINE Terbinafine ► Orally & topically effective drug against candida & dermatophytes ► Fungicidal : shorter courses of therapy required & low relapse rates ► Pharmacokinetics: ► Well absorbed orally 75% ► Highly keratophilic & lipophilic ► High protein bound , poor BBB permeability ► t1/2- 15 days ► Negligible effect on CYP450 Terbinafine (Contd.) ► ► Adverse events: ► Nausea , vomiting , Diarrhoea ► Taste disturbances ► Rarely hepatic dysfunction ► Topical: itching , dryness , rashes etc 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 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 Spectrum of Action (Contd.) ► Nystatin: Candidiasis only ► Griseofulvin: Dermatophytosis only ► Terbinafine : Dermatophytosis & candidiasis ► Caspofungin: Aspergillosis & candidiasis