Antifungal agents

Medicinal Chemistry and Pharmacology of Antifungal Agents and how to take care from fungal infections. Useful Course study material for the undergraduate , postgraduate and aspirants of Pharmacy , Pharmacology and Medicinal Chemistry.

1. ANTIFUNGAL DRUGS Dr. Amit G. Nerkar , M.Pharm , PhD., CCP., FAFSER Founder and Director, Ateos Foundation of Science Education and Research, Pune, M.S., India

2.   Fungi is: Eukaryotic – a true nucleus Do not contain chlorophyll Have cell walls Produce filamentous structures Produce spores Contain ergosterol The Term mycosis (plural: mycoses) refers to conditions in which fungi pass the resistance barriers of the human or animal body and establish infections.

3. A yeast infection results from an overgrowth of yeast (a type of fungus) anywhere in the body.  Candidasis  is by far the most common type of yeast infection. There are more than 20 species of  Candida , the most common being  Candida albicans . These fungi live on all surfaces of our bodies. Under certain conditions, they can become so numerous they cause infections, particularly in warm and moist areas. Examples of such infections are vaginal yeast infections, thrush (infection of tissues of the oral cavity), skin, including diaper rash, beneath large breasts, and nailbed infections. Candida infections commonly occur in warm moist body areas, such as underarms. Usually your skin effectively blocks yeast, but any breakdown or cuts in the skin may allow this organism to penetrate. Typical affected areas in babies  include the mouth and diaper areas. Vaginal yeast infection, which is the most common form of  Vaginitis  is often referred to as vaginal Candidiasis . In adults, oral yeast infections become more common with increased age. Adults also can have yeast infections around dentures, in skin folds under the breast and lower abdomen, nailbeds , and beneath other skin folds. Most of these candida infections are superficial and clear up easily with treatment. Infections of the nailbeds often require prolonged therapy. Rarely, the yeast infection may spread throughout the body. In systemic candidal disease (in which the fungus enters the bloodstream and spreads throughout the body), up to 45% of people may die. Even common mouth and vaginal yeast infections can cause critical illness and can be more resistant to normal treatment. Yeast infections that return may be a sign of more serious diseases such as diabetes, leukemia, or AIDS.

4. damp.

5. Targets for Antifungal agents Generally these targets should be different from mammalians. Both human and fungi are eukaryotic, so not much difference could be found. The most important difference is the presence of cell wall for fungi that is not found in humans. Other targets are: Inhibitors of DNA synthesis. Disruption of mitotic spindle. Interfere with metabolism. The most exploited difference is the nature of sterols: Important components of cell membrane for proper function of cell membrane enzymes and ion transporter proteins.

6. Targets for Antifungal agents

7. , Terbinafine

8. Mechanism of action of antifungal Agents

9. Targets for Antifungal agents Mammalians contain cholesterol while fungi posses ergosterol. The difference is in the side chain of ergosterol which is more flat compared to cholesterol; A difference that is responsible for providing selectivity for the majority of antifungal agents. Cholesterol Ergosterol

10. Polyene membrane disrupters Polyenes : macrocyclic lactones with distinct hydrophilic and lipophilic regions. Produced from Streptomyces species Hydrophilic: alcohol, carboxylic acids, sugar. Lipophilic: contain a pharmacophore of 4-7 conjugated double bonds. The number of the double bonds correlate directly to activity and inversely to toxicity. Amphotericin is 10X more active which can be taken systemically. Mechanism of action: have affinity to ergosterols containing membranes, then inserted in the cell membrane, disrupts its function, leak of cell components.

11. Amphotericin

12. Polyene membrane disrupters 1- Nystatin : - A tetraene agent that used topically. - No oral absorption, so used orally for mouth and GIT infections. 2- Amphotericin B : - Heptaene derivative with low enough toxicity for I.V use, but still toxic drug used with caution. - It does not cross BBB, so used intrathecally of brain fungal infections. - The main side effect is nephrotoxicity, reduced by formulation change. - Liposomal encapsulation was found to target infected tissues as the capillary size at the infected areas is larger, so release the drug specifically at that area.

13. Nystatin Amphotericin nephrotoxicity

14. Ergosterol Biosynthesis inhibitors A- Azoles : - The largest group of antifungal agents. - Some used topically and others used systemically. - some are orally bioavailable with broad spectrum properties. - SAR: - 5-membered ring with 2-3 Ns. - side chain attached to N. - At least has one aromatic ring. - Mechanism of action: - Act by inhibiting ergosterol synthesis by inhibiting CYP450 14- α - demethylase , where the basic nitrogen N3 of the drug bind to heme iron of the enzyme blocking the active site.

15. Mechanism of action of Azoles

16. Ergosterol Biosynthesis inhibitors - Inhibition will lead to accumulation of sterols with extra methyl group. - This new sterol structure does not have the shape and physical properties of the normal ones, leading to permeability changes. - Selectivity to mammalian C450 compared to the fungal one is 1:1000, and even, most of azoles considered mammalian C450 inhibitors which lead to serious drug-drug interactions in some cases. - Systemic azoles are : Ketoconazole, Itraconazole , Fluconazole and voricanazole . - Non-systemic azoles are : Clotrimazole , Oxiconazole and miconazole .

17. Ergosterol Biosynthesis inhibitors Ketoconazole : - Imidazole derivative, that is orally active for systemic infections. - Depends mainly on low stomach pH for absorption. - Inhibit C450 causing serious drug-drug interactions. - All its metabolites are inactive and mainly used topically.

18. Ergosterol Biosynthesis inhibitors Ketoconazole Metabolism: - Deacylation. - Aromatic hydroxylation. Hydroxylation Binds heme active site Deacylation

19. Ergosterol Biosynthesis inhibitors 2- Itraconazole : - Triazole derivative. - Oral bioavailability depend on food and stomach pH. - highly interfere with liver enzymes (serious drug drug interactions). 3- Fluconazole : - Equal bioavailability, oral and I.V. - Could cross BBB (Why?). - Weak inhibitor to some liver enzymes.

20. Ergosterol Biosynthesis inhibitors B- Allylamines : - They have limited spectrum of activity which is only used for dermatophytes. - Includes: Naftifine, Terbinafine, and Tolnaftate - Mechanism of action: inhibit squalene epoxidase, - leading to build up of squalene that it self is toxic compound. - and also lead to reduction of sterol levels in cell membrane, leading to cell lysis. - Mammalian squalene epoxidase is less sensitive to these drugs.

21. Ergosterol Biosynthesis inhibitors -Terbinafine : - Topical and Oral. - Active against many dermatophytes. - Highly lipophilic. - Extensively metabolized.

22. Ergosterol Biosynthesis inhibitors C- Morpholines : - Amorolfine : - The only drug of this class, used topically. - Act on Δ 14 reductase enzyme, and Δ 8 , Δ 7 isomerase enzymes. - produce non-similar compounds with different physical properties, leading to cell leakage.

23. Miscellaneous mechanism of actions Flucytosine : Powerful agent for systemic infections. Taken up by fungal cells and interferes with DNA synthesis Prodrug to produce 5-flurouracil. Griseofulvin : Orally taken for superficial infections. Not used topically. Bind to protein tubulin. Interfere with cell division.

24. Chemical Classification……………..

25. Chemical Classification….. contd …

26. Mixed Classification:

27. ANTIFUNGAL ANTIBIOTICS: Amphotericin B Nystatin Griseofulvin

28. Polyene antifungal: hydrophobic hydrophilic Polyene antifungals :- A polyene is a circular molecule consisting of a hydrophobic and hydrophilic region. The polyene antimycotics bind with sterols in the fungal cell membrane, principally ergosterol . As a result, the cell's contents leak out (usually the hydrophilic contents) and the cell dies. Animal cells contain cholesterol instead of ergosterol and so they are much less susceptible. (Note: as polyene's hydrophobic chain is reduced, its sterol binding activity is increased. Therefore, increased reduction of the hydrophobic chain may result in it binding to cholesterol, making it toxic to animals.)

29. Chemistry : Polyene antifungal: hydrophobic hydrophilic

30. Structure activity relationship (SAR): Polyene antifungal Antibiotics : hydrophobic hydrophilic

31. Polyene antifungal: Structure activity relationship (SAR): The polyene antibiotic produced by actinomycetes contain alarge lactone ring with 4 to 7 unsubstituted conjugated double bond . The conjugated system are usually in all-trans configuration so that the ring contains a planner lipophilic segment and a less rigid hydrophilic portion. With increase conjugation (double bond) the activity and toxicity will increase. The polyenes have polyhydroxyl groups .

32. Structure activity relationship (SAR): Amphotericin B have 7conjugated double bond while nystatin have 6 conjugated double bond so, amphotericin B more active and more toxic. Most polyene antifungal drugs are macrocyclic lactones. Ring sizes varying from 12 to 37 atoms in size . Polyene antifungal:

33. Amphtericin B Nystatin

34. polyene antifungal drug. Used intravenously for systemic fungal infections. It was originally extracted from Streptomyces nodosus , a filamentous bacterium. There areTwo amphotericins: Amphotericin A and Amphotericin B only B is used clinically. Amphtericin B

35. Amphtericin B Uses and spectrum: Amphotericin B for injection (IV) administered primarily to patients with progressive, potentially life-threatening fungal infections such as: Aspergillosis cryptococcosis (torulosis) North American blastomycosis systemic candidiasis coccidioido-mycosis histoplasmosis zygomycosis including mucormycosis Its spectrum is the broadest of all antifungals.

36. Amphotericin B : Antifungal Spectrum

37. Amphtericin B Precaution: Acute reactions including fever, shaking chills, hypotension, anorexia, nausea, vomiting, headache, and tachypnea are common 1 to 3 hours after starting an intravenous infusion. Rapid intravenous infusion. Whenever medication is interrupted for a period longer than 7 days, therapy should be resumed by starting with the lowest dosage level. Pregnancy: Teratogenic Effects, category B. Nursing Mothers Pediatric Use

38. Amphtericin B Contraindication: This product is contraindicated in those patients who have shown hypersensitivity to Amphotericin B or any other component in the formulation.

39. Amphtericin B Pharmacokinetic: Poorly absorbed from GIT. Start with small initial dose then gradually increase it. An elimination half-life approximately 15 days. Amphotericin B circulating in plasma is highly bound (>90%) to plasma proteins. Amphotericin B is excreted very slowly (over weeks to months) by the kidneys. After treatment is discontinued, the drug can be detected in the urine for at least seven weeks .

40. Amphtericin B Side effects: acute reaction: fever shaking chills hypotension anorexia nausea vomiting headache dyspnea tachypnea

41. Side effects Nephrotoxicity (kidney damage). Electrolyte imbalances (e.g. hypokalemia and hypocalcemia). Increased liver enzymes and hepatotoxicity up to acute liver failure. several forms of anemia. serious cardiac arrhythmias. Skin reactions. Amphtericin B

42. Amphtericin B Drug interaction: Flucytosine Diuretics or Cisplatin  Corticosterioids Cytostatic drugs  Foscarnet, Ganciclovir, Tenofovir, Adefovir

43. Drug interaction: Nephrotoxic medications: agents such as aminoglycosides, cyclosporine, and pentamidine. Imidazoles (e.g., ketoconazole, miconazole, clotrimazole, fluconazole, etc.) Skeletal muscle relaxants. Digitalis glycosides. Amphtericin B

44. Nystatin Drug description: Nystatin is an antimycotic polyene antibiotic obtained from Streptomyces noursei. Nystatin is a polyene antifungal drug to which many molds and yeast infections are sensitive, including Candida spp. Nystatin has some toxicity associated with it when given intravenously, but it is not absorbed across intact skin or mucous membranes.

45. It is considered a relatively safe drug for treating oral or gastrointestinal fungal infections. It is only insoluble in water and sparingly soluble in organic solvent. It is unstable to moisture, heat and light. Administered orally in the treatment of gastrointestinal candidiasis and oral thrush, intestinal monilial infection. Drug of choice for vaginal & cutaneous candidiasis. Administered in vaginal tablets or topically, sometimes combined with iodochlorohydroxyquine.

46. This product is available in the following dosage forms: Suspension Tablet Capsule Spectrum and Uses: Nystatine has awide spectrum of antifungal activity, nystatine used for Cutaneous, vaginal, mucosal and esophageal Candida infections. Cryptococcus is also sensitive to nystatin. treating neonatal oral thrush.

47. Brand names: Nystan Infestat Nystalocal Nystamont Nystop PRECAUTION: General This medication is not to be used for the treatment of systemic mycoses. Discontinue treatment if sensitization or irritation is reported during use. Carcinogenesis, Mutagenesis, Impairment of Fertility: There also have been no studies to determine mutagenicity or whether this medication affects fertility in males or females.

48. Pregnancy: Teratogenic Effects: Category C. Animal reproduction studies have not been conducted with nystatin oral suspension. Nystatin oral suspension should be given to a pregnant woman only if clearly needed. Nursing Mothers: It is not known whether nystatin is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when nystatin is administered to a nursing woman.

49. SIDE EFFECTS: Nystatin is well tolerated even with prolonged therapy. Oral irritation and sensitization have been reported. Gastrointestinal : Diarrhea ,nausea, vomiting, gastrointestinal upset/disturbances. Dermatologic : Rash, including urticaria has been reported rarely. Other: Tachycardia, bronchospasm, facial swelling.

50. Pharmacokinetics: Gastrointestinal absorption of nystatin is insignificant (poorly absorbed). Most orally administered nystatin is passed unchanged in the stool. In patients with renal insufficiency significant plasma concentrations of nystatin may occur. Microbiology: Nystatin is both fungistatic and fungicidal gainst a wide variety of yeasts and yeast-like fungi. Candida albicans demonstrates no significant resistance to nystatin on repeated subculture in increasing levels of nystatin other Candida species become quite resistant.

51. OVERDOSE: Oral doses of nystatin in excess of five million units daily have caused nausea and gastrointestinal upset. CONTRAINDICATION: The preparation is contraindicated in patients with a history of hypersensitivity to any of its components.

52. Non polyenes antifungals Griseofulvin : The drug binds to tubulin , interfering with microtubule function, thus inhibiting mitosis. It binds to keratin in keratin precursor cells and makes them resistant to fungal infections. It is only when hair or skin is replaced by the keratin- griseofulvin complex that the drug reaches its site of action. Griseofulvin will then enter the dermatophyte through energy dependent transport processes and bind to fungal microtubules. This alters the processing for mitosis and also underlying information for deposition of fungal cell walls.

53. Brand Names: Fulvicin P/G, Fulvicin U/F, Grifulvin V, Gris-PEG, Grisactin 250, Grisactin 500, Grisactin Ultra Penicillium niciklium griseofulvum . Spectrum of activity and Resistance: 1) Effective against various species of Trichophyton , Microsporum, and Epidermophyton 2) Not effective against candida and bacteria Griseofulvin

54. Structure Activity Relationship: Four possible stereoisomers only (+)- enantiomer is active Cl replaced by F → same activity Cl replaced by Br or H → ↓ activity Placement of the halogen on C5 → ↓ activity Replacement of CH 3 O on ring C with either propoxy or butoxy functions → ↑ activity

55. Mechanism of action : Binds to keratin disrupts the cell's mitotic spindle structure cause defective DNA synthesis interferes with tubulin polymerization Resistance: is due to alteration of the drug's target site, by mutation of ribosome sequences. Griseofulvin

56. Uses: is effective against dermatophytes but yeast-like fugi are less susceptible. Tinea capitis (ringworm of the scalp) Tinea cruris (ringworm of the high) Tinea corporis (ringworm of the body ( Tinea unguium (onychomycosis) Tinea barbae (barber's itch) Tinea : species of fungus that causes ringworm Griseofulvin

57. Griseofulvin Side effects: Skin rashes Dizziness Fatigue Headache Vomiting Swelling Loss of taste sensation Tingling in the hands or feet Oral thrush (yeast infection of the mouth)

58. Drug interactions: cause drug stop its absorption. Antacids and H2 antagonists nausea and vomiting alcohol (thinning the blood less than required) because Griseofulvin increase liver enzyme reducing the concentration of warfarin Warfarin (increasing the chance of pregnancy) because Griseofulvin cause increase in liver enzyme reducing the concentration of Oral contraceptive Oral contraceptive

59. Pharmacokinetic: Oral Diatery fat increase absorption Half life 9-21 hours Demethylated and conjugated with glucuronide Precautions: use machines or do other things that could be dangerous if you are dizzy. Stay out of direct sunlight . . Griseofulvin

60. Griseofulvin Amphotericin B Nystatin Loss of taste sensation Tingling ,Oral thrush Nephrotoxicity, hepatotoxicity, cardiac arrhythmias & anemia SE: Oral irritation and sensitization Binds to keratin>>> disrupts mitotic spindle structure>>>defective DNA synthesis>>> interferes with tubulin polymerization MOA: bind to ergosterol in cell memb. >>> leakage of ions >>> cell death. oral IV ROA: topical,and orally widely SOU: widely

61. Classification of antifungals Examples: * Natamycin -- 33 Carbons, binds well to ergosterol * Rimocidin * Nystatin * Amphotericin B

62. Natamycin 33 Carbons Natamcyin is able to inhibit growth of fungi by inhibiting transport of amino acids and glucose across the plasma membrane. Natamycin performs this function by specifically binding to  ergosterol and inhibiting membrane transport proteins. Natamycin has a very low solubility in water; however, natamycin is effective at very low levels. Its minimum inhibitory concentration is less than 10  ppm  for most molds. Natamycin was first isolated in 1955 from fermentation broth of a  Streptomyces natalensis  cell culture. It is applied topically as a cream, in eye drops, or (for oral infections) in a lozenge. It shows negligible absorption into the body when administered in these ways. When taken orally, little or none is absorbed from the gastrointestinal tract, making it inappropriate for systemic infections Natamycin , also known as  pimaricin , is an antifungal medication used to treat fungal infections around the eye. This includes infections of the eyelids, conjunctiva, and cornea.  It is used as eye drops. [ Natamycin is also used in the food industry as a preservative.

63. Hamycin is obtained from a strain of  streptomyces  bacteria growing in soil i.e.,  Streptomyces pimprina . This compound is being produced in India by Hindustan Antibiotics Limited, located at Pimpri , Pune , Maharashtra, India. It is similar to nystatin and it is more water-soluble. Hamycin Hamycin  is a  polyene antimycotic  organic compound described in India. It is a heptaene  antifungal compound rather similar in chemical structure to  amphotericin B except that it has an additional aromatic  groupbonded to the molecule. When pure, hamycin is a yellow, powdered solid. There are two versions of hamycin with very similar chemical structures: Hamycin A and Hamycin B

64. ANTIMETABOLITES: Flucytosine

65. 5-Flucytosine Flucytosine by mouth is used for the treatment of serious infections caused by susceptible strains of  Candida or  Cryptococcus neoformans . It can also be used for the treatment of  chromomycosis  ( chromoblastomycosis ), if susceptible strains cause the infection. Flucytosine must not be used as a sole agent in life-threatening fungal infections due to relatively weak antifungal effects and fast development of resistance, but rather in combination with amphotericin B and/or  azole   antifungals such as  fluconazole  or  itraconazole . Minor infections such as candidal  cystitis may be treated with flucytosine alone. In some countries, treatment with slow intravenous infusions for no more than a week is also a therapeutic option, particular if the disease is life- threatening.Serious fungal infections may occur in those who are immunocompromised . These people benefit from combination therapy including flucytosine , but the incidence of side-effects of a combination therapy, particular with amphotericin B, may be higher.

66. MOA- Two major mechanisms of action have been elucidated: Flucytosine is intrafungally converted into the cytostatic fluorouracil which undergoes further steps of activation and finally interacts as 5-fluorouridinetriphosphate with RNA biosynthesis thus disturbing the building of certain essential proteins. Flucytosine also undergoes conversion into 5-fluorodeoxyuridinemonophosphate which inhibits fungal DNA synthesis. Spectrum of susceptible fungi and resistance Flucytosine is active  in vitro  as well as  in vivo  against some strains of  Candida  and  Cryptococcus . Limited studies demonstrate that flucytosine may be of value against infections with  Sporothrix ,  Aspergillus ,  Cladosporium ,  Exophila , and  Phialophora . Resistance is quite commonly seen as well in treatment-naive patients and under current treatment with flucytosine . In different strains of  Candida  resistance has been noted to occur in 1 to 50% of all specimens obtained from patients. 5-Flucytosine

67. AZOLES Imidazoles : Ketoconazole,clotrimazole , oxiconazole , miconazole Triazoles : Floconazole , Itraconazole Voriconazole , Posaconazole

68. Imidazole and triazole antifungals The imidazole and triazole antifungal drugs inhibit the enzyme cytochrome P450 14α-demethylase. This enzyme converts lanosterol to ergosterol , and is required in fungal cell membrane synthesis. These drugs also block steroid synthesis in humans. * Miconazole ( Miconazole nitrate) * Clotrimazole - marketed as Lotrimin The triazoles are newer, and are less toxic and more effective * Fluconazole * Itraconazole

69. Azoles Mechanism of Action

70. Azoles Ketoconazole , Miconazole , clotrimazole , Oxiconazole

71. Ketoconazole 1-[4-[4-[[(2R,4S)-2-(2,4-dichlorophenyl)-2-(imidazol-1-ylmethyl)-1,3-dioxolan-4-yl] methoxy ] phenyl ] piperazin -1-yl] ethanone

72. Ketoconazole Uses:

73. Miconazole Uses Miconazole is used to treat skin infections such as athlete's foot, jock itch, ringworm, and other fungal skin infections ( candidiasis ). This medication is also used to treat a skin condition known as pityriasis ( tinea versicolor ), a fungal infection that causes a lightening or darkening of the skin of the neck, chest, arms, or legs. Miconazole is an azole  antifungal that works by preventing the growth of fungus. This medication is used to treat  vaginal yeast infections . Miconazole reduces vaginal  burning , itching , and discharge that may occur with this condition.  How to use Miconazole Nitrate 2 % Topical Cream Use this medication on the skin only. Clean and thoroughly dry the area to be treated. Apply this medication to the affected skin, usually twice a day or as directed by your doctor. If you are using the spray form, shake the bottle well before applying. Dosage and length of treatment depends on the type of infection being treated. Do not apply this more often than prescribed.  1-{2-[(2,4-Dichlorobenzyl)oxy]-2-(2,4-dichlorophenyl)ethyl}-1H-imidazole nitrate

74. Clotrimazole Clotrimazole  is used to treat skin infections such as athlete's foot, jock itch, ringworm, and other fungal skin infections ( candidiasis ). This medication is also used to treat a skin condition known as pityriasis ( tinea versicolor ), a fungal infection that causes a lightening or darkening of the skin of the neck, chest, arms, or legs. Clotrimazole is an azole  antifungal that works by preventing the growth of fungus. How to use Clotrimazole Solution Use this medication on the skin only. Clean and thoroughly dry the area to be treated. Apply this medication to the affected skin, usually twice a day or as directed by your doctor. Dosage and length of treatment depends on the type of infection being treated. 1-[(2-Chlorophényl)( diphényl ) méthyl ]-1H-imidazole  

75. Oxiconazole Oxiconazole  (trade names  Oxistat  in the US,  Oxizole  in Canada) is an antifungal medication typically administered in a cream or lotion to treat skin infections, such as athlete's foot, jock itch and ringworm. It can also be prescribed to treat the skin rash known as  tinea versicolor , caused by systemic yeast overgrowth ( Candida  spp.). (Z)-1-(2,4-dichlorophenyl)-N-[(2,4-dichlorophenyl) methoxy ]-2-imidazol-1-ylethanimine;nitric acid

76. AZOLES Triazoles : Fluconazole , Itraconazole Voriconazole

77. Triazoles   First-generation Itracon-azole and fluconazole were some of the first triazoles synthesized, but had limitations associated with their use. Second-generation triazoles such as voriconazole , posaconazole , albaconazole , efinaconazole , ravuconazole and isavuconazole are all derivatives of either itraconazole or fluconazole .

78. Fluconazole 2-(2,4-difluorophenyl)-1,3-bis (1,2,4-triazol-1-yl) propan-2-ol

79. Fluconazole Uses:

80. Itraconazole 4-[4-[4-[4-[[2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-l] methoxy ] phenyl] -1-piperazinyl]phenyl]-2,4-dihydro-2-(1-methylpropyl)-3H-1,2,4-triazol-3-one

81. Itraconazole Uses

82. Voriconazole (α R, β S)- α-(2,4,- difluorophenyl )-5-fluoro- β- methyl- α-(1 H-1,2,4-triazol-1-yl-methyl)-4-pyrimidineethanol

83. Voriconazole

84. Posaconazole 4-[p-[4-[p-[[(3R,5R)-5-(2,4-Difluorophenyl)tetrahydro-5-(1H-1,2,4-triazol-1-ylmethyl)-3-furyl] methoxy ] phenyl]-1-piperazinyl]phenyl]-1-[(1S,2S)-1-ethyl-2-hydroxypropyl]- Δ2-1,2,4- triazolin-5-one

85. Invasive Aspergillus & Candida Infections Oral suspension or delayed-release tablets are indicated for prophylaxis of invasive Aspergillus and Candida infections in patients who are at high risk of developing these infections due to being severely immunocompromised ( eg , hematopoietic stem cell transplant recipients with GVHD, hematologic malignancies with prolonged neutropenia from chemotherapy) Oral suspension: 200 mg (5 mL ) PO TID Tablet: 300 mg PO BID on Day 1, then 300 mg PO qDay IV: 300 mg IV BID on Day 1, then 300 mg IV qDay (see IV preparation and administration) Duration of therapy is based on recovery from neutropenia or immunosuppression Oropharyngeal Candidiasis Oral suspension is indicated for oropharyngeal candidiasis 100 mg (2.5 mL ) PO BID on Day 1, then 100 mg PO qDay for 13 days Refractory to itraconazole and/or fluconazole : 400 mg (10 mL ) PO BID; duration based on severity of underlying disease and clinical response

86. ALLYAMINES: Terbinafine , Butenafine

87. Terbinafine

88. Butenafine Butenafine hydrochloride  is a synthetic benzyl amine antifungal. Butenafine is indicated for the topical treatment of tinea ( pityriasis ) versicolor due to  Malassezia furfur , as well as athlete's foot ( Tinea pedis ), ringworm ( Tinea corporis ) and jock itch ( Tinea cruris ) due to  Epidermophyton floccosum ,  Trichophyton mentagrophytes ,  Trichophyton rubrum , and  Trichophyton tonsurans . It also displays superior activity against  Candida albicans  than terbinafine and  naftifine . Butenafine demonstrates low minimum inhibitory concentrations against  Cryptococcus  and  Aspergillus . There is some evidence that it is effective against dermatophyte infections of the toenails, but needs to be applied daily for prolonged periods (at least one year). Butenafine is typically available as a 1% topical cream. Like the allylamine antifungals , butenafine works by inhibiting the synthesis of  ergosterol  by inhibiting  squalene epoxidase , an enzyme responsible for the creation of sterols needed in fungal cell membranes. Lacking ergosterol , the cell membranes increase in permeability, allowing their contents to leak out.

89. Naftifine Naftifine has triple action: antifungal, antibacterial and anti-inflammatory. Its precise mechanism of action is unknown, but may involve selectively blocking sterol biosynthesis via inhibition of the squalene 2,3-epoxidase enzyme.The half-life is approximately 2–3 days.The metabolites are excreted in the urine and feces. Naftifine is an allylamine  antifungal drug for the topical treatment of  tinea pedis ,  tinea cruris , and  tinea corporis  (fungal infections) (E)-N-Methyl-N-(3-phenyl-2-propenyl)-1-naphthalenemethanamine

90. Echinocandins Caspofungin , anidulafungin , micafungin

91. Echinocandins

92. History Discovery of echinocandins stemmed from studies on papulacandins isolated from a strain of  Papularia sphaerosperma  (Pers.), which were liposaccharide - i.e., fatty acid derivatives of a disaccharide that also blocked the same target, 1,3-β glucan synthase - and had action only on  Candida  spp. (narrow spectrum). Screening of natural products of fungal fermentation in the 1970s led to the discovery of echinocandins , a new group of antifungals with broad-range activity against  Candida  spp. One of the first echinocandins of the pneumocandin type, discovered in 1974, echinocandin B, could not be used clinically due to risk of high degree of hemolysis . Screening semisynthetic analogs of the echinocandins gave rise to cilofungin , the first echinofungin analog to enter clinical trials, in 1980, which, it is presumed, was later withdrawn for a toxicity due to the solvent system needed for systemic administration. The semisynthetic pneumocandin analogs of echinocandins were later found to have the same kind of antifungal activity, but low toxicity. The first approved of these newer echinocandins was caspofungin , and later micafungin and anidulafungin were also approved. All these preparations so far have low oral bioavailability, so must be given intravenously only. Echinocandins have now become one of the first-line treatments for  Candida  before the species are identified, and even as antifungal prophylaxis in hematopoietic stem cell transplant patients.

93. Echinocandins Chemistry The present-day clinically used echinocandins are semisynthetic pneumocandins , which are chemically lipopeptide in nature, consisting of large cyclic ( hexa ) peptoid . Caspofungin , micafungin , and anidulafungin are similar cyclic hexapeptide antibiotics linked to long modified N-linked acyle fatty acid chains. The chains act as anchors on the fungal cell membrane to help facilitate antifungal activity. Due to their limited oral bioavailability, echinocandins are administered through intravenous infusion.

94. Echinocandins Advantages of echinocandins : broad range (especially against all  Candida ), thus can be given empirically in febrile neutropenia and stem cell transplant can be used in case of azole -resistant  Candida  or use as a second-line agent for refractory aspergillosis long half-life ( polyphasic elimination: alpha phase 1–2 hours + beta phase 9–11 hours + gamma phase 40–50 hours) low toxicity: only histamine release (3%), fever (2.9%), nausea and vomiting (2.9%), and phlebitis at the injection site (2.9%), very rarely allergy and anaphylaxis not an inhibitor, inducer, or substrate of the cytochrome P450 system, or P-glycoprotein, thus minimal drug interactions lack of interference from renal failure and hemodialysis no dose adjustment is necessary based on age, gender, race better (or no less effective) than amphotericin B and fluconazole against yeast infections

95. Disadvantages of Echinocandins Disadvantages of echinocandins : embryotoxic in animal studies (category C) thus should be avoided if possible in pregnancy needs dose adjustment in liver disease poor ocular penetration in fungal endophthalmitis

96. Caspofungin Echinocandins noncompetitively inhibit beta-1,3-D-glucan synthase enzyme complex in susceptible fungi to disturb fungal cell glucan synthesis. Beta- glucan destruction prevents resistance against osmotic forces, which leads to cell lysis . They have fungistatic activity against  Aspergillus  species. and fungicidal activity against most  Candida spp., including strains that are fluconazole -resistant.  In vitro  and mouse models show echinocandins may also enhance host immune responses by exposing highly antigenic beta- glucan epitopes that can accelerating host cellular recognition and inflammatory responses.

97. Caspofungin

98. Anidulafungin Anidulafungin is manufactured via semisynthesis . The starting material is  echinocandin B (a  lipopeptide  fermentation product of  Aspergillus nidulans  or the closely related species,  A. rugulosus ), which undergoes deacylation (cleavage of the  linoleoyl  side chain) by the action of a deacylase enzyme from the bacterium  Actinoplanes utahensis  in three subsequent synthetic steps, including a chemical reacylation , the antifungal drug anidulafungin  is synthesized. Candidemia  and other forms of invasive  Candida  infections (intra-abdominal abscess and peritonitis) Esophageal candidiasis Anidulafungin has not been studied in  endocarditis ,  osteomyelitis , and meningitis due to  Candida , and has not been studied in sufficient numbers of  neutropenic patients to determine efficacy in this group. Indications

99. Other topical Antifungals : Tolnaftate , Undecylenic Acid, Benzoic Acid, Haloprogin

100. Haloprogin Haloprogin Haloprogin was previously used in 1% topical creams as an antifungal agent. It was marketed over-the-counter primarily to treat  tinea  infections of the skin. The mechanism of action is unknown. Haloprogin had a high incidence of side effects including: irritation, burning, vesiculation (blisters), scaling, and itching. It has since been discontinued due to the emergence of more modern antifungals with fewer side effects.

101. Tolnaftate , Ciclopirox , Benzoic acid Tolnaftate  is a synthetic  thiocarbamate  used as an anti-fungal agent that may be sold without medical prescription in most jurisdictions. It is supplied as a cream, powder, spray, and liquid aerosol. Tolnaftate is used to treat fungal conditions such as jock itch, athlete's foot and ringworm.

102. Ciclopirox Ciclopirox is indicated for the treatment of  tinea pedis  and  tinea corporis  due to  Trichophyton rubrum ,  Trichophyton mentagrophytes  and  Epidermophyton floccosum , as well as  seborrheic dermatitis. It is not to be used in the eyes or vagina, and nursing women should consult their doctors before use, since it is not known whether ciclopirox passes into human milk.

103. Topical Agents in Dermatophytosis

104. Topical Agents in Dermatophytosis

105. Clinical Spectrum of Antifungals

106. Important Features