antifungal drugs

1. Antifungal agents

2. INTRODUCTION
• These are the drugs which kill or inhibit the growth of funqus in the body of
the host and are used for superficial and deep (systemic) mycoses. Some
fungal infections are self-limiting (get cured without treatment).
Clinically fungal infections in animals can be classified into two groups:
• Superficial fungal infections: Include dermatophytoses of the skin, hair and
nails (caused by Trichophyton, Microsporum or Epidermophyton spp) and
candidiasis or moniliasis of the moist skin and mucous membrane (GIT and
genital tract).
• Systemic (Deep) mycoses: Systemic fungal infections
(Coccidioidiomycosis, histoplasmosis, cryptococcsis, candidiasis or
blastomycosis etc).

3. • Antifungal agents can be classified in two groups based on their mode
application:
• Systemic Agents: These are used in the treatment of fungal infections of
internal organs or GIT. Some of these may also be useful in treating
dermatomycoses (via blood and enter keratin producing cells in the skin).
• Topical Agents: These are used for treating superficial fungal infections,
usually applied topically. Griseovulvin is used to treat dermatomycoses, but
administered orally (after absorption enters in the keratin producing cells in
the skin via the circulation). A topical agent used for dermatophytoses
should have both fungistatic and keratolytic properties; otherwise it should
be combined with a keratolytic agent so that it can remove the keratin layer
and facilitate the surface contact of the drug and the fungus.

4. CLASSIFICATION
1. Antibiotics:
A. Polyenes: Amphotericin B (AMB), Nystatin, Hamycin, Natamycin
(Pimaricin)
B. Heterocyclic benzofuran: Griseofulvin
2. Antimetabolite : Flucytosine (5-FC)
3. Azoles:
A. Imidazoles (topical): Clotrimazole, Econazole, Miconazole, Oxiconazole
(systemic): Ketoconazole
B. Triazoles (systemic): Fluconazole, Itraconazole, Voriconazole
4. Allylamine: Terbinafine
5. Other topical agents: Tolnaftate, Undecylenic acid, Benzoic acid,
Quiniodochlor, Ciclopiroxolamine, Butenafine, Sod. thiosulfate.

5. POLYENE ANTIBIOTICS
• The name polyene is derived from their highly double-
bonded structure. Amphotericin B is described as the
prototype.
Amphotericin B (AMB)
It is obtained from Streptomyces nodosus.
Chemistry
• 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. A polar aminosugar and a carboxylic acid group are
present at one end in some. They are all insoluble in water
and unstable in aqueous medium.

6. Mechanism of action

7. Mechanism of action
Amphotericin B
Binds ergosterol in fungal cell membrane
Form pores in cell membrane
Cell contents leak out
Cell death

8. 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.

9. • Fungal Resistance:
– Replacement of ergosterol by other sterols in fungal plasma
membrane.
– Resistance is not a problem clinically.

10. 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

11. Uses
• 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:

12. Adverse effects:
• Acute reaction:
Chills, fever, headache, pain all
over, nausea, vomiting, dyspnoe 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

13. 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:
– 5 lac U in intestinal moniliasis TDS
– 1 lac U in vaginitis
– Prevention of oral candidiasis
– Can be used in oral, cutaneous, conjunctival candidiasis
• Adverse events:
• Gastointestinal disturbances with oral tablets

14. Hamycin:
• S. Pimprina
• Hindustan antibiotics pimpri
• More water soluble, fraction absorbed orally but unreliable in systemic
infections
• Topical use in thrush, cutaneous candidiasis, trichomonas & monilial
vaginitis, otomycosis by Aspergillus
Natamycin:
• Similar to nystatin, broad spectrum
• Used topically 1%, 3% ointment
• Fusarium solani keratitis, trichomonas & monilial vaginitis

15. Griseofulvin
One of early antibiotics from penicillium griseofulvum
• Fungistatic, systemic drug for superficial fungal infections
• Active against most dermatophytes
• Dermatophytes concentrate it actively henceselective toxicity
• Resistance: loss of concentrating ability

16. Mechanism of action:
• Griseofulvin interacts with
polymerized microtubules and
disrupts the mitotic spindles thus
arresting fungal mitosis

17. 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

18. Adverse effects:
• Headache most common
• GIT disturbances
• CNS symptoms: confusion, fatigue, vertigo
• Peripheral neuritis
• Rashes, photoallergy
• Transient leukopenia, albuminuria

19. 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

20. 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

22. • 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

23. • 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

24. Mechanism of action

25. 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

26. Adverse effects
• 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

27. 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

28. 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

29. Itraconazole
• Broadest spectrum of activity also against aspergillus
• Fungistatic but effective in immunocompromised
• Does not inhibit steroid hormone synthesis and no serious hepatoxicity

30. Uses
• DOC for paracoccidomycosis & chromoblastomycosis
• DOC for histoplasmosis & blastomycosis
• Esophageal, oropharyngeal vaginal candidiasis
• Dermatophytosis: less effective than fluconazole
• Onychomycosis : 200 mg / day for 3 months
• Aspergillosis: 200 mg OD/ BD with meals for 3 months or more

31. Topical agents used in dermatophytosis
• 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

32. • 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)
• Quinidiochlor;
– Luminal amoebicide
– Weak antifungal & antibacterial
– External application : dermatophytosis , mycosis barbae, pitryasis
versicolor
• Selenium sulfide: T versicolor
• Potassium iodide: Dermatophytic infection

33. Systemic administration Topical
Griseofulvin Ketoconazole
Ketoconazole Miconazole
Fluconazole Clotrimazole
Itraconazole Terbinafine
Terbinafine Nystatin

34. Important characteristics
• 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