pharmacology of anti-fungal drugs

1. Antifungals
Dr.M.Zabihi
PhD of Pharmacology
Shahid Sadoughi University of Medical Sciences, Yazd, Iran

2. Introduction
• 200,000 known species of fungi (yeasts, molds, mushrooms, smuts)
• the pathogens : Aspergillus fumigatus and Candida albicans
• the source of penicillin, Penicillium chrysogenum
• only ~400 fungi cause disease in animals
– even fewer cause significant human disease
• fungal infections are becoming more common
– AIDS
– compromised immune systems
• Fungi are eukaryotes
• unique cell walls (containing glucans and chitin)
• different strategies for eradication
1. synthesis of membrane and cell-wall components
2. membrane permeability
3. synthesis of nucleic acids
4. microtubule/mitotic spindle function

4. Introduction
• Systemic and topical
• systemically or topically : imidazole, triazole, and polyene
antifungals
• many superficial mycoses can be treated either systemically
or topically
• Pneumocystis jirovecii
• life-threatening pneumonia in immunocompromised patients
• a fungus and not a protozoan
• antibacterial or antiprotozoal rather than antifungal

6. Systemic Antifungal Agents - Amphotericin B
• Polyene macrolide
• Binding and interaction ergosterol in the membrane
• Polyenes appear to form pores or channels
• increases the permeability of the membrane
• leakage of a variety of small molecules
• Candida spp., Cryptococcus neoformans, Blastomyces
dermatitidis, Histoplasma capsulatum, Sporothrix schenckii,
Coccidioides spp., Paracoccidioides braziliensis, Aspergillus spp.,
Penicillium marneffei, and mucormycosis

7. Systemic Antifungal Agents - Amphotericin B
• limited activity against protozoa
• Leishmania spp. , Naegleria fowleri
• No antibacterial activity
• Fungal Resistance
• replace ergosterol with certain precursor sterols
• Nystatin or Amphotericin B

8. Systemic Antifungal Agents - Amphotericin B
• Therapeutic Uses
• Intrathecal infusion : Meningitis caused by Coccidioides
• Fever and headache are common reactions that may be decreased by intrathecal
administration of 10-15 mg of hydrocortisone
• Local injections into a joint or peritoneal dialysate fluid
• Intraocular injection : endophthalmitis
• IV injection
• choice for mucormycosis
• used for initial treatment of cryptococcal meningitis
• severe or rapidly progressing histoplasmosis, blastomycosis, coccidioidomycosis, and
penicilliosis marneffei
• in patients not responding to azole therapy of invasive aspergillosis, extracutaneous
sporotrichosis, fusariosis, alternariosis, and trichosporonosis
• patients with neutropenia who have fever that does not respond to broad-spectrum
antibacterial agents over 5-7 days

9. Systemic Antifungal Agents - Amphotericin B
• Adverse effects
• The major acute reactions to IV : fever and chills
• Febrile reactions abate with subsequent infusions
• Tachypnea and respiratory stridor or modest hypotension also may occur
• but true bronchospasm or anaphylaxis is rare
• Patients with pre-existing cardiac or pulmonary disease : hypoxia or hypotension
• Nephrotoxicity
• Azotemia : 80%
• Toxicity is dose-dependent and usually transient
• increased by concurrent therapy with other nephrotoxic agents
• aminoglycosides or cyclosporine
• Renal tubular acidosis and renal wasting of K+ and Mg2+
• Supplemental K+ is required in one-third of patients on prolonged therapy
• Saline loading has decreased nephrotoxicity, even in the absence of water or salt deprivation
• Hypochromic, normocytic anemia
• most likely due to decreased production of erythropoietin
• Headache, nausea, vomiting, malaise, weight loss, and phlebitis at peripheral infusion sites are common
• Thrombocytopenia or mild leukopenia (rarely)

10. Systemic Antifungal Agents - Flucytosine
• 5-fluorocytosine
• a fluorinated pyrimidine related to fluorouracil and floxuridine
• All susceptible fungi deaminate flucytosine to 5-fluorouracil
• 5-FU is a potent antimetabolite
• DNA synthesis is impaired as the ultimate result of this latter reaction
• The lack of cytosine deaminase in mammalian cells
• The selective action of flucytosine
• prevents metabolism to fluorouracil

11. Systemic Antifungal Agents - Flucytosine
• Antifungal Activity
• Cryptococcus neoformans, Candida spp., chromoblastomycosis
• concentration in CSF is ~65-90% of plasma
• penetrates into the aqueous humor
• Therapeutic Uses
• predominantly in combination with amphotericin B
• cryptococcal meningitis in AIDS patients
• Untoward Effects
• Bone marrow suppression : leukopenia , thrombocytopenia
• complication with an underlying hematological disorder, radiation or drugs that injure the
bone marrow, or a history of treatment with such agents
• rash, nausea, vomiting, diarrhea, severe enterocolitis
• plasma levels of hepatic enzymes are elevated
• reverses when therapy is stopped

12. Systemic Antifungal Agents - Azoles
• Imidazoles
• clotrimazole, miconazole, ketoconazole, econazole, butoconazole,
oxiconazole, sertaconazole, sulconazole
• Triazoles
• terconazole, itraconazole, fluconazole, voriconazole,
posaconazole
• Mechanism of Action
• inhibition of 14-α-sterol demethylase, a microsomal CYP
• impair the biosynthesis of ergosterol for the cytoplasmic
membrane

13. Systemic Antifungal Agents - Azoles
• Antifungal Activity
• Candida spp., Cryptococcus neoformans, Blastomyces dermatitidis,
Histoplasma capsulatum, Coccidioides spp., Paracoccidioides brasiliensis,
ringworm fungi (dermatophytes)
• intermediate in susceptibility : Aspergillus spp., Scedosporium apiospermum
(Pseudallescheria boydii), Fusarium, Sporothrix schenckii
• more resistant : Candida krusei, mucormycosis
• do not have any useful antibacterial or antiparasitic activity
• with the possible exception of antiprotozoal effects against Leishmania major
• Posaconazole has slightly improved activity in vitro against mucormycosis
• Resistance
• Aspergillus fumigatus
• Cryptococcus neoformans

14. Systemic Antifungal Agents - Azoles
• Interactions
• The azoles interact with hepatic CYPs as substrates and inhibitors
• azoles can elevate plasma levels of some drugs
• Warfarin, alprazolam, buspirone, cisapride, digoxin, eplerenone, ergot alkaloids,
fexofenadine, haloperidol, losartan, lovastatin, methadone, phenytoin, omeprzole,
quinidine, pimozide, risperidone, sildenafil, solifenacine, zolpidem, vinca alkaloids,
cyclosporine, carbamazepine, …..
• Some co-administered drugs can decrease plasma concentrations of
azoles
• combinations of certain drugs with azole antifungal medications may be
contraindicated
• Such as clopidogrel, thioridazine and tetrabenazine with fluconazole

16. Systemic Antifungal Agents - Ketoconazole
• replaced by itraconazole for all mycoses
• except when the lower cost of ketoconazole outweighs the advantage of
itraconazole
• Itraconazole lacks ketoconazole's corticosteroid suppression
• expanding the antifungal spectrum
• sometimes is used to inhibit excessive production of G.Cs in
patients with Cushing's syndrome

17. Systemic Antifungal Agents - Itraconazole
• Therapeutic Uses
• choice in nonmeningeal infections due to B. dermatitidis, H. capsulatum
• useful in invasive aspergillosis outside the CNS
• particularly after the infection has been stabilized with amphotericin B
• Approximately half the patients with distal subungual onychomycosis
respond to itraconazole
• oropharyngeal and esophageal candidiasis
• more GI side effects than fluconazole tablets
• reserved for patients not responding to fluconazole

18. Systemic Antifungal Agents - Itraconazole
• Untoward Effects
• interactions with many other drugs
• potentially fatal cardiac arrhythmias with quinidine, pimozide, cisapride
• Serious hepatotoxicity
• GI side effects (common)
• Diarrhea, abdominal cramps, anorexia, nausea
• Anaphylaxis (rarely), including Stevens-Johnson syndrome

19. Systemic Antifungal Agents - Fluconazole
• completely absorbed from the GI tract
– Plasma concentrations are essentially the same whether the drug is given orally or IV
• its bioavailability is unaltered by food or gastric acidity
• Renal excretion accounts for >90% of elimination
• diffuses readily into body fluids, including breast milk, sputum, saliva
• concentrations in CSF can reach 50-90% of plasma
• The dosage interval should be increased from 24-48 hours

20. Systemic Antifungal Agents - Fluconazole
• Therapeutic Uses
• Candidiasis
• Empirical treatment of febrile neutropenia
• Cryptococcosis
• not effective
• histoplasmosis, blastomycosis, sporotrichosis
• Aspergillosis
• Mucormycosis (As with other azoles, with the possible exception of posaconazole)

21. Systemic Antifungal Agents - Fluconazole
• Untoward Effects
• >7 days of drug : nausea, headache, skin rash, vomiting, abdominal pain, diarrhea
• prolonged therapy at 400 mg daily : Reversible alopecia
• hepatic failure or Stevens-Johnson syndrome (Rare)
• During pregnancy : Category C

22. Systemic Antifungal Agents - Voriconazole
• Genetic polymorphisms in CYP2C19 can cause up to 4-fold
differences in drug exposure
• Drug Interactions
• When starting voriconazole in a patient receiving 40 mg/day of
omeprazole, the dose of omeprazole should be reduced by half

23. Systemic Antifungal Agents - Voriconazole
• Therapeutic Uses
• superior efficiency to Amphotericin B in the primary therapy of invasive
aspergillosis
• esophageal candidiasis
• non-neutropenic patients with candidemia
• Untoward Effects
• Contraindicated in pregnancy (Category D)
• well tolerated
• Hepatotoxicity have been reported, liver function should be monitored
• Prolongation of the QTc interval (like some other azoles)
• significant in patients with other risk factors for torsades de pointes
• Visual effects
• Transient visual or auditory hallucinations (after the first dose, at night, IV)
• Anaphylactoid reactions

24. Systemic Antifungal Agents - Posaconazole
• an analog of itraconazole
• with the same broad antifungal spectrum
• up to 4-fold greater activity in vitro against yeasts and filamentous fungi,
(mucormycosis)
• Genetic polymorphisms in CYP2C19
• Drugs that reduce gastric acid decreased posaconazole exposure
by 32-50%
• e.g., cimetidine and esomeprazole

25. Systemic Antifungal Agents - Posaconazole
• Therapeutic Use
• oropharyngeal candidiasis
• fluconazole is the preferred drug
• prophylaxis against candidiasis and aspergillosis in patients >13 years of age
who have prolonged neutropenia or severe graft-vs-host disease (GVHD)
• In aspergillosis as itraconazole and voriconazole
• mucormycosis
• Untoward Effects
• The safety profile of posaconazole is good
• The most common : nausea, vomiting, diarrhea, abdominal pain, headache
• pregnancy Category C

26. Systemic Antifungal Agents - Echinocandins
• The inhibition of glucan synthesis
• reduces structural integrity of the fungal cell wall
• resulting in osmotic instability and cell death
• Caspofungin
• Anidulafungin
• Micafungin

27. Systemic Antifungal Agents - Echinocandins
• Lack of oral bioavailability
• inability to penetrate into CSF
• Lack of renal clearance
• Minimal adverse effects
• Pregnancy Category : C

28. Systemic Antifungal Agents - Caspofungin
• Therapeutic Use
• initial therapy of deeply invasive candidiasis
• salvage therapy of invasive aspergillosis
• in failing or intolerant of approved drugs, such as amphotericin B or voriconazole
• Esophageal candidiasis
• persistently febrile neutropenic patients with suspected fungal infections
• Untoward Effects
• Well tolerated
• phlebitis at the infusion site
• Histamine-like effects

29. Systemic Antifungal Agents - Griseofulvin
• insoluble in water
• inhibits microtubule function
• a prominent morphological manifestation:
• the production of multinucleate cells as the drug inhibits fungal mitosis
• improved absorption with a fatty meal
• Griseofulvin is deposited in keratin precursor cells
• the new growth of hair or nails is the first to become free of disease

30. Systemic Antifungal Agents - Griseofulvin
• Antifungal Activity
• Fungistatic
• for various species of the dermatophytes Microsporum, Epidermophyton,
and Trichophyton
• no effect on bacteria or on other fungi
• Therapeutic Uses
• Mycotic disease of the skin, hair, and nails
• choice for tinea capitis in children
• Tinea of the hands and beard
• Highly effective in tinea pedis

31. Systemic Antifungal Agents - Griseofulvin
• Untoward Effects
• headache (incidence as high as 15%)
• peripheral neuritis, lethargy, mental confusion, impairment of performance of routine tasks, fatigue,
syncope, vertigo, blurred vision, transient macular edema, and augmentation of the effects of alcohol
• Nausea, vomiting, diarrhea, heartburn, flatulence, dry mouth, and angular stomatitis
• Hepatotoxicity
• leukopenia, neutropenia, punctate basophilia, and monocytosis
• often disappear despite continued therapy
• Blood studies should be carried out at least once a week during the first month of treatment or longer
• Common renal effects include albuminuria and cylindruria without evidence of renal insufficiency
• Reactions involving the skin are cold and warm urticaria, photosensitivity, lichen planus, erythem
• Serum sickness syndromes and severe angioedema (rare)
• induces hepatic CYPs
• warfarin dose adjustment
• Reduces the efficacy of low-estrogen OCPs

32. Systemic Antifungal Agents - Terbinafine
• inhibition of fungal squalene epoxidase, blocking ergosterol biosynthesis
• Increased intracellular squalene also impairs cell growth
• is well absorbed
• Proteins bind >99%
• Drug accumulates in skin, nails, and fat
• is not recommended in patients with azotemia or hepatic failure

33. Systemic Antifungal Agents - Terbinafine
• is well tolerated
• low incidence of GI distress, headache, or rash
• Very rarely : fatal hepatotoxicity, severe neutropenia, Stevens-
Johnson syndrome, toxic epidermal necrolysis
• pregnancy Category : B
• it is recommended that systemic terbinafine therapy for onychomycosis
be postponed until after pregnancy is complete
• more effective for nail onychomycosis than itraconazole
• Terbinafine also is effective in tinea capitis

34. Topical Antifungal Agents
• useful in many superficial fungal infections
• stratum corneum, squamous mucosa, or cornea
• include dermatophytosis (ringworm), candidiasis, tinea versicolor, piedra, tinea nigra, and fungal keratitis
• is not successful for mycoses of the nails (onychomycosis) and hair (tinea capitis) and subcutaneous
mycoses, such as sporotrichosis and chromoblastomycosis
• Imidazoles and Triazoles for Topical Use
• ringworm, tinea versicolor, mucocutaneous candidiasis
• Cutaneous Application
• should be applied twice a day for 3-6 weeks
• Vaginal Application
• for vaginal candidiasis
• once a day for 1-7 days, preferably at bedtime to facilitate retention
• clotrimazole, miconazole, and terconazole
• for 3-7 days
• The most common side effect : vaginal burning or itching
• Oral Use
• Use of the oral troche of clotrimazole is properly considered as topical therapy
• The only indication : oropharyngeal candidiasis

35. Topical Antifungal Agents - Clotrimazole
• Fungicidal concentrations remain in the vagina for as long as 3 days after
application of the drug
• Untoward Effects
• Skin : stinging, erythema, edema, vesication, desquamation, pruritus, and urticarial
• Vaginal : mild burning sensation, abdominal cramps (Rare), increase in urinary
frequency, or skin rash
• oral : GI irritation

36. Topical Antifungal Agents - Miconazole
• Adverse effects
• Vagina : burning, itching, irritation
• infrequently, pelvic cramps (0.2%), headache, hives, or skin rash
• Skin : Irritation, burning, maceration
• safe in pregnancy
• although some authors avoid its vaginal use during the first trimester

37. Topical Antifungal Agents
• Ketoconazole
• skin dermatophytes infections, tinea versicolor, seborrheic dermatitis
• Tolnaftate
• most cutaneous mycoses
• ineffective against Candida
• Toxic or allergic reactions to tolnaftate have not been reported
• Pruritus is usually relieved in 24-72 hours
• Terbinafine
• Tinea
• Less active against Candida species and Malassezia furfur
• Cutaneous candidiasis and tinea versicolor

38. Topical Antifungal Agents
• Nystatin (Polyene Antifungal agent)
– Nystatin was discovered in the New York State Health Laboratory and was
named accordingly
– structurally similar to amphotericin B, and has the same mechanism of
action
– is not absorbed from the GI tract, skin, or vagina
– only for candidiasis
– well tolerated

39. Topical Antifungal Agents
• Undecylenic Acid
– primarily fungistatic
– against a variety of fungi, including those that cause ringworm.
– various dermatomycoses, especially tinea pedis
• Benzoic Acid and Salicylic Acid
– Whitfield's ointment : An ointment containing benzoic and salicylic acids
in a ratio of 2:1 (usually 6-3%)
– the fungistatic action of benzoate with the keratolytic action of salicylate
– mainly in tinea pedis
– Mild irritation may occur at the site of application