Anti fungal agents

Anti-Fungal Agents

1. Anti- F ungal A gents Jagir R. Patel Asst Professor Dept. Pharmacology

2. Introduction Fungi are a diverse kingdom of unicellular- and multicellular eukaryotic organisms that replicate either by simple mitosis or by spore formation. F ungal cells consist of 4 parts (listed from innermost to outermost ) PART DESCRIPTION CYTOPLASM - contains membrane-bound organelles including a nucleus-bound genetic material (in opposition to bacterial cytoplasm that neither contains membrane-bound organelles nor a nucleus). CELL MEMBRANE - consists of a lipoprotein membrane containing ergosterol that stabilizes the lipoprotein membrane (in opposition to human cell membranes that contain cholesterol, and bacterial cell membranes that do not contain any sterols whatsoever (except mycoplasma)). CELL WALL - composed of beta-D-glucan and chitin (in opposition to bacterial cell walls that are composed of peptidoglycan, and human cells that do not have a cell wall whatsoever).

3. CAPSULE - a polysaccharide coat present only in some fungal species. Ergosterol of the fungal cell membrane is synthesized from squalene by an extremely complicated biochemical pathway too vast to cover here however, this pathway is extremely important pharmacologically, fungal infections (“mycoses”) occur in subjects with a decreased defense against fungal colonization, including decreased immune defense system and decreased normal bacterial flora.

4. Groups of Fungal infections Y easts (e.g. Cryptococcus neoformans ) Y east-like fungi that produce a structure resembling a mycelium (e.g. Candida albicans ) F ilamentous fungi with a true mycelium (e.g. Aspergillus fumigatus ) ‘dimorphic’ fungi that, depending on nutritional constraints, may grow as either yeasts or filamentous fungi (e.g. Histoplasma capsulatum ).

5. Superficial Fungal I nfections CANDIDIASIS General information C aused by candida albicans Affected Sites 1. Dermal candidiasis 2. Oral candidiasis 3. vaginal candidiasis

6. Dermatomycosis General information “dermatophytosis” C aused by epidermopyhton, trichophyton and/or microsporium (collectively known as “dermatophytes”) Affected Sites Tinea corporis (affects any skin site except the ones listed immediately below) Tinea capitis (affects the scalp) Tinea cruris (affects the groin) Tinea pedis (affects the feet) Tinea unguium (affects the nails)

7. Tinea cruris

8. Tinea Capitis Tinea Unguium

9. DEEP FUNGAL INFECTIONS “Systemic fungal infections”: may affect any internal tissue organ

10. Classification Antibiotics Polyenes : Amphotericin B, Nystatin, Hamycin, Natamycin Heterocyclic benzofuran : mitotic inhibitors: Griseofulvin 2. Anti-metabolite : Pyrimidine analogues or thymidylate synthase inhibitors: Flucytosine 3. Azoles : cell wall inhibitors Imidazoles: Clotrimazole, Econazole, Miconazole, Oxiconazole, luliconazole, Sertaconazole, Sulconazole, Tioconazole

11. Systemic : ketoconazole Triazoles : Systemic : fluconazole, Itraconazole, Voriconazole, Isoconazole, Posaconazole Allyamine : Terbinafine, Naftifine 5 . Other topical agents : Tolnaftate, undecylenic acid, Benzoic acid, Quiniodochlor

12. Targets of antifungal agents

13. Mechanism of resistance Each species can display a specific molecular mechanism of resistance to antifungal drug however, four mechanisms are common and can function synergistically: 1. Altered drug metabolism 2. Mutations in gene encoding target proteins 3. Prevented entry of the drug 4. Removal of the drug from the cell through the upregulation of the expression of multidrug efflux pumps. Mutations in cytosine permease (uptake) or deficiency in enzymes implicated in the metabolism of fluoropyrimidines are a frequent cause of antifungal drug resistance. Mutations in ERG11 or in FKS1 (which encodes the β-1, 3-glucan synthase), result in resistance to azoles and Echinocandins, respectively.

14. Amphotericin Spectrum : It is active against Aspergillus spp Basidiobolus spp B. dermatitidis Candida spp C. neoformans Mucor spp

15. Aminopetricin (polyenes) possess a macro cyclic ring , one side of which has several conjugated double bonds & is highly lipophilic , while the other side is hydrophilic with OH groups they are insoluble in water & unstable in aqueous medium . Polyene antifungal such as amphotericin B act by binding to ergosterol in the fungal cell membrane. This binding results in depolarization of the membrane and formation of pores (there, they require hydrophobic interaction b/w the lipophilic segment of the polyenes antibiotic & the sterol) that increase permeability to proteins, aminoacids & other water soluble sub and monovalent and divalent cations moves out, i.e leakage of the cell, & the pore disrupts the membrane functions, eventually leading to cell death. Amphotericin B may also induce oxidative damage in fungal cells and has been reported to stimulate of host immune cells

16. Cholesterol present in the host cell membrane closely resembles ergosterol ; the polyenes bind to it as well, though with lesser affinity. Thus the selectivity of the polyenes is low. Amb is one of the most toxic systematically used antibiotics, though it is a least toxic polyenes .

17. Resistance: Mechanisms of resistance to polyenes in fungal species has come from studies using mutants generated by ( i.e decrease in the conc. of the ergosterol) Growing cells in the presence of increasing concentrations of antifungal agents (multistep mutants). Pharmacokinetics Absorption: Little or no absorption from the GI tract (oral). Distribution: Distributed widely, CSF (small quantities). Excretion: Via urine (small amounts); not removed by dialysis; 24 hr (elimination half-life); may be increased to 15 days in long-term treatment.

18. Adverse reactions Topical : Local irritation, pruritus and skin rash. IV infusion : Fever, chills, convulsions, malaise; nausea, vomiting, diarrhoea, anorexia; tinnitus, vertigo, hearing loss; hypotension, hypertension, cardiac arrhythmias; peripheral neuropathy; phlebitis, pain at Inj site, disturbances in renal function and renal toxicity. Potentially Fatal: Anaphylactic reaction; leucoencephalopathy. Overdosage can result in cardio-respiratory arrest. Indications Oral candidiasis Severe systemic fungal infections Severe meningitis Aspergillosis Endocarditis Candiduria

19. Nystatin It is poorly absorbed from GIT and not absorbed from Skin or mucous membrane. It is highly toxic for systemic use ADV: nausea and bitter taste, hypersensitive reactions Indications For candida infections only Topically for oral, Oropharyngeal, corneal, conjunctival, and cutaneous candidiasis As oral tablet for intestinal candidiasis and superinfection due to candida In vaginal candidiasis as vaginal suppositories

20. Griseofulvin Mechanism of action Griseofulvin inhibits fungal cell division at metaphase. Griseofulvin interferes with mitosis; multi nucleated and stunted fungal hyphae, results from its actions. It causes abnormal metaphase configurations. it does not cause metaphase arrest rather the daughter nuclei fail to move apart or move only a short distance. It does not inhibit polymerization of tubulin, but binds polymerized microtubules and somehow disorients them. It binds to human keratin , making it resistant to fungal infections; may also interfere w/ deoxyribonucleic acid (DNA) production .

21. MOA

22. Pharmacokinetics Absorption: Variably and incompletely absorbed from the GI tract; may be increased by decreasing particle size and admin w/ fatty meals. Time to peak plasma concentrations: W/in 4 hr. Distribution : Deposited in keratin precursor cells and concentrated in stratum corneum of the skin and in the nail and hair . Plasma protein-binding: Approx 84% (mainly albumin). Metabolism: Hepatically metabolised to 6-demethylgriseofulvin and its glucuronide conjugates. Excretion: Via urine (mainly as metabolites, <1% as unchanged drug); faeces (large amount as unchanged drug); some in sweat. Elimination half-life: 9-24 hr.

23. Adverse reactions Skin rashes, urticaria, GI disturbances, dry mouth, taste alteration, headache, angioedema, leucopenia and other blood dyscrasias, proteinuria, oral candidiasis, peripheral neuropathy, photosensitisation, dizziness, confusion, depression, impaired coordination, insomnia, fatigue, exacerbation of SLE. Potentially Fatal : Severe skin reactions (e.g. Stevens-Johnson syndrome, toxic epidermal necrolysis, erythema multiforme ) H epatotoxicity Drug interaction: May reduce the efficacy of phenylbutazone, sedative and hypnotic drugs, and coumarin anticoagulants. Decreased GI absorption w/ barbiturates . Indications  Oral: Dermatophytosis, (hair and skin infections); up to 6 mth (fingernail infections); ≥12 mth (toenail infections).

24. Anti-metabolites: Flucytosine Spectrum: Flucytosine (5-FC) is a synthetic pyrimidine antimetabolite that is often used in combination with amphotericin B. This combination of drugs is administered for the treatment of systemic mycoses and for meningitis caused by Cryptococcus neoformans and Candida albicans .

25. 5-FC enters fungal cells via a cytosine-specific “permeases” an enzyme not found in mammalian cells. 5-FC is then converted by a series of steps to 5-fluorodeoxyuridine 5' monophosphate. This false nucleotide inhibits thymidylate synthase, thus depriving the organism of thymidylic acid an essential DNA component. The unnatural mononucleotide is further metabolized to a trinucleotide (5-fluorodeoxyuridine 5'-triphosphate) and is incorporated into fungal RNA, thus disrupting nucleic acid and protein synthesis.

26. Resistance Resistance due to decreased levels of any of the enzymes in the conversion of 5-FC to 5-fluorouracil (5-FU) and beyond, or increased synthesis of cytosine, can develop during therapy. This is the primary reason that 5-FC is not used as a single antimycotic drug. The rate of emergence of resistant fungal cells is lower with a combination of 5-FC plus a second antifungal agent than it is with 5-FC alone

27. Pharmacokinetics Absorption : Absorbed rapidly and almost completely from the GI tract . Distribution: Widely distributed in body tissues and fluids, including CSF. Crosses the placenta. Metabolism : Undergoes minimal hepatic metabolism into 5-FU via deamination in yeasts and probably by gut bacteria. Excretion : Via urine Adverse drugs reactions 5-FC causes reversible neutropenia, thrombocytopenia, and dose-related bone marrow depression. Gastrointestinal disturbances, such as nausea, vomiting, and diarrhea, are common, and severe enterocolitis may occur . Potentially Fatal: Bone marrow toxicity, acute hepatic injury.

28. Drug interactions May result in synergistic effect when combined w/ amphotericin B or fluconazole. May increase phenytoin plasma levels. Indications In severe systemic candidiasis, cryptococcal meningitis , and other severe infections, it is usually given in combination w/ amphotericin B or fluconazole.

29. Azoles Cell wall Inhibitors Spectrum : Imidazoles and Triazoles have broad spectrum of antifungal activity covering dermatophytes, Candida , other fungi involved in deep mycosis. Norcardia , some gram +ve organism and anaerobic bacteria i.e. Stap.aureus, Sterp.faecilis, and leishmania .

30. Mechanism of action They are fungi static Azoles antifungals inhibit the fungal cytochrome P-450 3-A dependent enzyme 14 alpha demethylase, thereby interrupting the synthesis of ergosterol. Inhibition of this critical enzyme in the ergosterol synthesis pathway leads to the depletion of ergosterol in the cell membrane and accumulation of toxic intermediate sterols, causing increased membrane permeability and inhibition of fungal growth. The drug also inhibits the human gonadal & adrenal steroid synthesis, leading to the decreased production of the testosterone & adrenal steroid synthesis.

31. Ketoconazole ( prototype) Pharmacokinetics Absorption : Variably absorbed from the GI tract . Distribution : Widely distributed Metabolism : Partially hepatic via CYP3A4 converted to inactive metabolites. Excretion : Via faeces (57%); urine

32. Adverse effects It is most toxic among other azoles Anorexia , vomiting, nausea are common side effects Ktz reduces synthesis of adrenal cortical steroids, testosterone & oestrogen thus causes gynaecomastia, oligospermia, loss of libido, and impotence in males. Irregularities in menstrual cycle, amenorrhea in females. Fatal side effects : hepatotoxicity, hypersensitivity reactions Drug interactions Hypoglycemia = KTZ + sulfonylureas KTZ + cyclosporine = potentiates nephrotoxicity KTZ+ Warfarin= increased risk of bleeding Indications Dermatophytosis topically for T.pedis, T. curis, T. corporis, T. vesicular Candidiasis : no systemic use as it is very toxic can be replaced by Triazoles Seborrhoeic dermatitis , versicolor; Skin fungal infections Soap, shampoo, cream

33. Clotrimazole Clotrimazole is a broad-spectrum antifungal which binds to phospholipids in the cell membrane altering cell wall permeability causing a loss in essential intracellular elements . Absorption:  Negligible through intact skin (topical); 3-10% (vaginal). Metabolism :  Hepatic; converted to inactive metabolites. Excretion :  Urine, faeces (as metabolites ). Adv: Topical: Erythema, stinging, irritation; hypersensitivity reactions; contact dermatitis. Oral: GI disturbances, dysuria, mental depression, elevated liver enzymes.

34. Drug interactions : Antagonism with Polyene antibiotics . Indications : 100 mg daily alternatively , apply 1, 2 or 10% cream . Oropharyngeal candidiasis Fungal otitis externa Skin fungal infections Vulvovaginal candidiasis

35. Miconazole General information Administered orally and/or dermally May not cross the blood-brain barrier Side effects Nausea, vomiting and/or diarrhea , cardiac dysrhythmias , hypersensitivity reactions leading to fever, skin rashes and/or pruritus Medical uses systemic and topical Oropharyngeal candidiasis, Intestinal candidiasis, Vulvovaginal candidiasis,   Skin fungal infections, Nail fungal infections

36. S ertaconazole Pharmacokinetics: absorption minimal from skin Adverse effects Contact dermatitis, dry skin, burning skin, application site reaction, skin tenderness, erythema, pruritus, vesiculation, hyperpigmentation . Indications : cutaneous Tinea pedis infection

37. Sulconazole Absorption: Absorbed percutaneously (approx 8.7%). Excretion: Primarily via urine. Adverse effects Itching, burning, stinging, redness, blistering, erythema, pruritus, irritation, tingling, skin oedema, dryness, scaling, fissuring, cracking, generalised red papules, severe eczema, pustulation, vesiculation, contact dermatitis, papular rash. Indications Tinea cruris; Tinea versicolor; Tinea corporis, Tenia pedis 1% cream

38. Fluconazole Spectrum: susceptible fungi including B. dermatitidis , Candida spp., C. immitis , C. neoformans , Epidermophyton spp., H. capsulatum , Micosporum spp., Trichophyton spp. Pharmacokinetics Absorption : Well absorbed from the GI tract. Bioavailability: ≥90% ( oral) Distribution : Widely distributed into body tissues and fluids. Enters breast milk . Excretion : Via urine Elimination half-life: Approx 30 hr

39. Adverse effects Abdominal pain, diarrhoea, flatulence, nausea, vomiting, taste disturbance Headache , dizziness leucopenia , thrombocytopenia Hyperlipidaemia increased liver enzyme values, alopecia, hypokalaemia, angioedema, and toxic epidermal necrolysis. Potentially Fatal : Hepatotoxicity. Rarely, Stevens-Johnson syndrome, anaphylaxis. Contraindicated in pregnancy : due to teratogenicity

40. Indications : 50-400mg/kg depending on infections Superficial mucosal candidiasis Vaginal candidiasis; Candidal balanitis Cutaneous candidiasis; Dermatophytosis; Pityriasis versicolor Systemic candidiasis ; Cryptococcal infections Prophylaxis of fungal infections in immunocompromised patients

41. Itraconazole Spectrum : Microsporum spp. Trichophyton spp. Candida spp. Aspergillus spp. Pharmacokinetics Absorption: Absorbed from the GI tract. Absorption is enhanced by acidic gastric environment Distribution: Widely distributed into the skin, pus, sebum, organs and tissues; CSF. Metabolism : converted to major metabolite (hydroxyitraconazole). Excretion: Via urine or bile (as inactive metabolites), faeces (3-18% as unchanged drug), stratum corneum and hair (small amounts ).

42. Adverse drug effects GIT disturbances, hepatotoxicity, headache, hypokalemia, Potentially Fatal: CHF, pulmonary oedema, hepatotoxicity. Drug interactions May increase the plasma concentrations of oral anticoagulants Precautions : Patient w/ risk factors for CHF Indications: 200mg oral Oesophageal candidiasis; Oral candidiasis Prophylaxis of fungal infections in immunocompromised patients Vulvovaginal candidiasis Pityriasis versicolor Tinea cruris; Tinea corporis Nail fungal infections Systemic fungal infections Tinea pedis infections

43. Allyamine: Terbinafine Spectrum: The drug is primarily fungicidal . Antifungal activity is limited to dermatophytes and Candida albicans . Mechanism of action: Terbinafine inhibits fungal squalene epoxidase , thereby decreasing the synthesis of ergosterol. This plus the accumulation of toxic amounts of squalene result in the death of the fungal cell. Note: Significantly higher concentrations of terbinafine are needed to inhibit human squalene epoxidase, an enzyme required for the cholesterol synthetic pathway.

44. Pharmacokinetics Absorption: Absorbed well from the GI tract with 40% bioavailability (oral), minimal absorption (topical ). Distribution : Distributed into stratum corneum of the skin, nail plate, hair (concentrations higher than plasma) and breast milk. Protein-binding: Extensive. Metabolism: Hepatic; converted to inactive metabolites. Excretion: Via urine Adverse effects Anorexia, nausea, abdominal pain, taste disturbances, diarrhoea, rash, urticaria. Potentially Fatal: Liver failure, Stevens-Johnson syndrome, neutropenia

45. Drug interactions : Terbinafine+ Rifampicin=Decreased terbinafine concentration Terbinafine+ cimetidine= increased terbinafine concentration Indications: Oral Dermatophytosis and infections due to candida sp. 250mg

46. Topical : Tolnaftate It is inactive against Candida spp or bacteria . Onset : 24-72 hr. Indications : Topical/Cutaneous Superficial dermatophyte infections; Pityriasis versicolor

47. Glucan synthesis inhibitors: Echinocandins Echinocandins are a new class of antifungal drugs are thus called "penicillin of antifungals " (a property shared with papulacandins) as penicillin has a similar mechanism against bacteria but not fungi Spectrum : They have fungistatic activity against Aspergillus species . F ungicidal activity against most Candida spp ., including strains that are fluconazole-resistant Caspofungin, Micafungin, and Anidulafungin

48. Mechanism of Action The glucan (Beta glucans are carbohydrate polymers that are cross-linked with other fungal cell wall components (The bacterial equivalent is peptidoglycan) synthesis inhibitors are, collectively, agents that are presumed to block fungal cell wall synthesis by inhibiting the enzyme 1,3-beta glucan synthase. Inhibition of this enzyme results in depletion of glucan polymers in the fungal cell, resulting in an abnormally weak cell wall unable to withstand osmotic stress.

49. Caspofungin Pharmacokinetics Distribution : Distributed into the liver, lung, spleen, and GI tract. Plasma protein binding: Approx 97%, mainly to albumin. Metabolism : Slowly metabolised in the liver via hydrolysis and N -acetylation. Excretion : Via urine

50. Adverse effects Potentially Fatal: Anaphylaxis, severe toxic epidermal necrolysis, Stevens-Johnson syndrome. Drug interactions : Reduced plasma concentration w/ rifampicin Indications Invasive Aspergillosis, invasive candidiasis Oesophageal candidiasis Empiric therapy for febrile neutropenic patients

51. Micafungin Pharmacokinetics Distribution : Rapidly distributed into body tissues. Metabolism : Metabolised by arylsulfatase to its catechol form and further metabolised by COMT to the methoxy form. Excretion : Mainly via faeces Adverse effects Potentially Fatal: Severe hepatic dysfunction, hepatitis or hepatic failure, anaphylaxis and anaphylactoid reactions, including shock. Drug interaction : May increase exposure of amphotericin B, and Itraconazole Indications: Prophylaxis of Candida infection in hematopoietic stem cell transplantation recipients. Oesophageal candidiasis, invasive candidiasis

52. Organism(s) responsible) Principal disease(s) Common drug treatments Yeasts Cryptococcus neoformans Meningitis Amphotericin, flucytosine, fluoconazole Yeast-like fungus Candida albicans Thrush (and other superficial infection) Systemic candidiasis Fluconazole, Itraconazole Echinocandins, fluconazole, amphotericin, other azoles

53. Organism(s) responsible) Principal disease(s) Common drug treatments Filamentous fungi Trichophyton spp. Epidermophyton floccosum Microsporum spp. Aspergillus fumigatus All these organisms cause skin and nail infections and are referred to as tinea or ‘ringworm’ Pulmonary aspergillosis Itraconazole Terbinafine, Griseofulvin Voriconazole, Amphotericin, Capsofungin Azoles

54. Organism(s) responsible) Principal disease(s) Common drug treatments Dimorphic fungi Histoplasma capsulatum Coccidioides immitis Blastomyces dermatides Histoplasmosis Coccidiomycosis Blastomycosis Itraconazole & amphotericin