This document provides an overview of antifungal agents, including their mechanisms of action, classifications, and clinical uses. Major antifungal classes discussed include azoles (e.g. fluconazole, itraconazole), polyenes (e.g. amphotericin B), echinocandins (e.g. caspofungin), and allylamines (e.g. terbinafine). It covers antifungals used to treat both superficial and systemic fungal infections, with details on selected drugs' mechanisms, spectra of activity, advantages/disadvantages, and adverse effect profiles.

1. ANTIFUNGAL AGENTS
Faraza Javed
Ph.D Pharmacology

2. Overview
 Infectious diseases caused by fungi are called
mycoses, and they are often chronic in nature.
 Fungi have rigid cell walls composed of chitin.
 The fungal cell membrane contains ergosterol
rather than the cholesterol found in mammalian
membranes.
 These chemical characteristics are useful in
targeting chemotherapeutic agents against
fungal infections

3.  Human fungal infections have increased
dramatically , owing mainly to advances
in surgery,cancer treatment, and critical
care accompanied by increases in use of
broad-spectrum antimicrobials and the
HIV epidemic.

4. Classification of anti fungals
A. According to MOA
1.Drug affecting synthesis / Function of cell
membrane
i. Synthesis (inhibit synthesis of ergosterol)
 Ketoconazole
 Fluconazole
 Itraconazole
 Voriconazole
 Miconazole
 Turbenafine

5. ii.Function
 Amphotericin B , Nystatin
2. Block nucleic acid synthesis
 Flucytosine
3. Distrupt microtubular function
 Griseofulvin
4. Reduction of fungal cell wall viability
Nikkomycin

6. B. According to route of administration
1. Topical :Nystatin Clotrimazole Econazole
Amphotericin B
2. Oral :Miconazole Ketoconazole Fluconazole
Itraconazole Flucytosine Grisofulvin
Terbenafine
3. I/V Amphotercin Miconazole Flucytozine
Fluconazole

7. C. According To chemical structure
1. Polyenes : Amphotericin B Nystatin
2. Pyrimidins: Flucytosine
3. Azoles: ketoconazole, miconazole,
Clotrimazole, fluconazole, voriconazole
4. Benzofurans:Griseofulvin
5. Miscellaneous drugs :
Undecylenic acid ,Benzoic acid , Salicylic acid
, Propionic acid , Caprylic acid

8. D. Therapeutic classification
1.Drugs for Subcutaneous and Systemic
Mycotic Infections
Amphotericin B Fluconazole
Itraconazole ketoconazole
voriconazole posaconazole
capsofungin micafungin
anidulafungin
2.Drugs for Cutaneous Mycotic Infections
Butoconazole , clotrimazole, Econazole
miconazole,griseofulvin,nystatin,terbinafine

9. Drugs for Subcutaneous and
Systemic Mycotic Infections
Amphotericin B
 It is a naturally occurring, polyene
macrolide antibiotic produced by
Streptomyces nodosus (polyene =
containing many double bonds; macrolide
= containing a large lactone ring of 12 or
more atoms.
 The drug is also sometimes used in
combination with flucytosine so that lower
(less toxic) levels of amphotericin B are
possible

10. Mechanism of action:
 Several amphotericin B molecules bind to
ergosterol in plasma membranes of sensitive
fungal cells.
 There, they form pores (channels) that require
hydrophobic interactions between the
lipophilic segment of polyene antibiotic and
the sterol .
 The pores disrupt membrane function,
allowing electrolytes (particularly potassium)
and small molecules to leak from the cell,
resulting in cell death

12. Clinical Use
 It is used as initial induction regimen for
serious fungal infections and is then
replaced by one of azole drugs for
chronic therapy or prevention of relapse.
 Such induction therapy is especially
important for immunosuppressed patients
and those with severe fungal pneumonia,
cryptococcal meningitis,with altered
mental status, or sepsis syndrome due to
fungal infection.

13.  It has also been used as empiric therapy for
selected patients in whom the risks of leaving
a systemic fungal infection untreated are high.
 The most common such patient is the cancer
patient with neutropenia who remains febrile
on broad-spectrum antibiotics.
 It is also used in treatment of Mycotic corneal
ulcers, Keratitis, Fungal arthritis.

14. LIPOSOMALAMPHOTERICIN B
 Therapy with amphotericin B is often limited
by toxicity, especially drug-induced renal
impairment.
 This has led to the development of lipid drug
formulations on assumption that lipid-
packaged drug binds to the mammalian
membrane less readily, permitting the use of
effective doses of drug with lower toxicity.

15.  Liposomal amphotericin preparations package
the active drug in lipid delivery vehicles.
 The lipid vehicle then serves as an
amphotericin reservoir, reducing nonspecific
binding to human cell membranes.
 This preferential binding allows for a
reduction of toxicity without sacrificing
efficacy and permits use of larger doses.
 Furthermore, some fungi contain lipases that
may liberate free amphotericin B directly at the
site of infection

16. Adverse Effects
INFUSION RELATED TOXICITY
 These include fever, chills, muscle spasms,
vomiting, headache, and hypotension.
 They can be reduced by slowing the infusion
rate or decreasing the daily dose.

17. Renal impairment:
 Despite low levels of drug excreted in urine,
patients may exhibit a decrease in glomerular
filtration rate and renal tubular function.
Creatinine clearance can drop, and potassium
and magnesium are lost.
 Nephrotoxicity may be potentiated by sodium
depletion; thus, a bolus infusion of normal
saline before and after amphotericin B infusion
may reduce incidence of drug-induced
nephrotoxicity.

18. Resistance
 Some isolates of Candida lusitaniae have
appeared to be relatively resistant to
amphotericin B.
 Aspergillus terreus may be more resistant to
amphotericin B than other Aspergillus
species.
 Mutants selected in vitro for nystatin or
amphotericin B resistance replace ergosterol
with certain precursor sterols.

19. Flucytosine
 Flucytosine (5-FC) is a synthetic pyrimidine
analog 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.

20. Mechanism of action
 5-FC enters fungal cells via a cytosine-
specific permease an enzyme not found in
mammalian cells and converted into
fluorouracil( 5-FU)
 The 5-FU is then converted to 5-fluorouracil-
ribose monophosphate (5-FUMP) and then is
either converted to 5-fluorouridine
triphosphate (5-FUTP) and incorporated into
RNA thus disrupting nucleic acid and protein
synthesis or converted by ribonucleotide
reductase to 5-fluoro-2'-deoxyuridine-5'-
monophosphate (5-FdUMP)

21.  (5-FdUMP) is a potent inhibitor of
thymidylate synthase thus depriving the
organism of thymidylic acid an essential DNA
component.
 Amphotericin B increases cell permeability,
allowing more 5-FC to penetrate the cell.
Thus, 5-FC and amphotericin B are
synergistic

23. Clinical Use
 Flucytosine is not used as a single agent
because of its demonstrated synergy with
other agents and to avoid the development of
resistance.
 It is used as combination therapy, either with
amphotericin B for cryptococcal meningitis or
with itraconazole for chromoblastomycosis.
 It is now common practice in HIV-negative
patients with cryptococcal meningitis to begin
with Amphotericin B plus flucytosine and
change to fluconazole after the patient has
improved

24. Adverse Effects
 The adverse effects of flucytosine result from
metabolism (possibly by intestinal flora) to
the toxic antineoplastic compound
fluorouracil.
 Bone marrow toxicity with anemia,
leukopenia, and thrombocytopenia are the
most common adverse effects
 A form of toxic enterocolitis can occur.

25. Resistance
 Resistance due to decreased levels of any of
enzymes in conversion of 5-FC to 5-
fluorouracil (5-FU) can develop during
therapy.
 This is the primary reason that 5-FC is not
used as a single antimycotic drug.

26. Azoles
 Are synthetic compounds that can be
classified as either imidazoles or triazoles
according to number of nitrogen atoms in
five-membered azole ring.
 Clotrimazole, miconazole, ketoconazole,
econazole, butoconazole, oxiconazole,
sertaconazole, and sulconazole are
imidazoles
 Terconazole, itraconazole, fluconazole ,
voriconazole, and posaconazole are triazoles .

27. Mechanism of action
 Azoles are predominantly fungistatic.
 They inhibit 14-alpha sterol demethylase (a
cytochrome P450 enzyme), thus blocking
demethylation of lanosterol to ergosterol the
principal sterol of fungal membranes and lead to
the accumulation of lanosterols.
 These lanosterols may disrupt close packing of
acyl chains of phospholipids, impairing functions
of certain membrane-bound enzyme systems such
as ATPase and enzymes of electron transport
system and thus inhibiting growth of the fungi.

29. Ketoconazole
 Ketoconazole was first oral azole introduced
into clinical use.
 It is distinguished from triazoles by its
greater tendency to inhibit mammalian
cytochrome P450 enzymes; that is, it is less
selective for fungal P450 than are newer
azoles.
 Oral administration has been replaced by
itraconazole for treatment of all mycoses
except when lower cost of ketoconazole
outweighs advantage of itraconazole.

30. Adverse effects
 In addition to allergies, dose-dependent
gastrointestinal disturbances, including
nausea, anorexia, and vomiting, are most
common adverse effects.
 Endocrine effects, such as gynecomastia,
decreased libido, impotence, and menstrual
irregularities, result from blocking of
androgen and adrenal steroid synthesis by
ketoconazole.
 Ketoconazole may accumulate in patients
with hepatic dysfunction. Plasma
concentrations of the drug should be
monitored in these individuals

31. Itraconazole
 It is an azole antifungal agent with a broad
antifungal spectrum.
 Itraconazole is available in oral and intravenous
formulations
 It lacks endocrinologic side effects of
ketoconazole.
 It is now drug of choice for treatment of
blastomycosis,sporotrichosis, histoplasmosis
oropharyngeal and esophageal candidiasis

32.  HIV-infected patients with disseminated
histoplasmosis have a decreased incidence of
relapse if given prolonged itraconazole
maintenance therapy
 Adverse effects include nausea and vomiting,
rash (especially in immunocompromised
patients), hypokalemia, hypertension, edema,
and headache.
 It should be avoided in pregnancy.
 It inhibits metabolism of many drugs,
including oral anticoagulants, statins, and
quinidine. Inducers of cytochrome P450
system increase metabolism of itraconazole.

33. Fluconazole
 It has no endocrinologic effects, because it does
not inhibit cytochrome P450 system responsible
for synthesis of androgens
 It is employed prophylactically, with some
success, for reducing fungal infections in
recipients of bone marrow transplants.
 It is drug of choice for Cryptococcus
neoformans,cryptococcal meningitis in patients
with AIDS after patient's clinical condition has
been stabilized with IV amphotericin B, for
candidemia, and for coccidioidomycosis

34.  It is effective against all forms of
mucocutaneous candidiasis.
 It is administered orally or intravenously.
 The adverse effects Nausea, vomiting, and
rashes headache
 It is teratogenic.
 It is an inhibitor of CYP3A4 and CYP2C9.
 It significantly increases plasma
concentrations of cisapride, cyclosporine,
phenytoin, sulfonylureas (glipizide,
tolbutamide, others), theophylline, and
warfarin

35. Voriconazole
 It is approved for treatment of invasive
aspergillosis,serious infections caused by
Scedosporium apiospermum and Fusarium
species.
 It has excellent activity against candida
species
 It is available for IV and oral administration.
 Observed toxicities include rash and elevated
hepatic enzymes.

36.  Visual disturbances are common and include
blurring and changes in color vision or
brightness.
 Voriconazole is metabolized by, and inhibits,
CYP2C19, CYP2C9 and CYP3A4.
 Coadministration with rifampin, ritonavir is
contraindicated because of accelerated
voriconazole metabolism.

37. Posaconazole
 It is a oral, broad-spectrum antifungal agent .
 It was approved in 2006 to prevent Candida
and Aspergillus infections in severely
immunocompromised patients and for
treatment of oropharyngeal candidiasis.
 Due to its spectrum of activity, posaconazole
could possibly be used in treatment of fungal
infections caused by Mucor species and other
zygomycetes.

38.  The most common side effects are GIT issues
(nausea, vomiting, diarrhea, and abdominal
pain) and headaches.
 It can cause an elevation of liver function tests
aspartate aminotransferase and alanine
aminotransferase.
 Concomitant use of posaconazole with ergot
alkaloids, pimozide, and quinidine is
contraindicated.

39. Echinocandins
 Are antifungal drugs that inhibit synthesis of
glucan in the cell wall via noncompetitive
inhibition of enzyme 1,3-β glucan synthase
 Beta glucans are carbohydrate polymers that
are cross-linked with other fungal cell wall
components .
 Three semi-synthetic echinocandin derivatives
have been developed for clinical use:
caspofungin, micafungin, and anidulafungin.

41. Caspofungin
 It is synthesized from fermentation product
of Glarea lozoyensis .
 This drug's spectrum is limited to Aspergillus
and Candida species
 Adverse effects include fever, rash, nausea,
and phlebitis
 It should not be co-administered with
cyclosporine.
 Caspofungin is a second-line antifungal for
those who have failed or cannot tolerate
amphotericin B or an azole.

42. Micafungin and anidulafungin
 Micafungin is produced from Coleophoma
empedri and anidulafungin is from Aspergillus
nidulans.
 Micafungin and anidulafungin have similar
efficacy against Candida species, but efficacy
for treatment of other fungal infections has not
been established.
 Also, they are not substrates for cytochrome
P450 enzymes and do not have any associated
drug interactions.

43. Drugs for Cutaneous Mycotic
Infections
Terbinafine
Mechanism of action
 It inhibits squalene, epoxidase thus blocking the
biosynthesis of ergosterol, an essential
component of fungal cell membranes.
 This inhibition also results in an accumulation
of squalene, result in the death of the fungal
cell.

45. Therapeutic uses
 It is fungicidal and drug of choice for treating
dermatophytoses and, especially,
onychomycoses (fungal infections of nails).
 It is better tolerated, requires shorter duration
of therapy, and is more effective than either
itraconazole or griseofulvin

46. Adverse effects
 The drug is well tolerated, with a low
incidence of gastrointestinal distress,
headache, or rash.
 The drug is contraindicated in pregnancy
(category B)
 Rifampin decreases blood levels of
terbinafine, whereas cimetidine increases
blood levels of terbinafine

47. Griseofulvin
 It is fungistatic.
 It is thought to inhibit fungal cell mitosis and
nucleic acid synthesis.
 It also binds to and interferes with function of
spindle and cytoplasmic microtubules by
binding to alpha and beta tubulin.
 It binds to keratin in human cells, then once it
reaches fungal site of action, it binds to
fungal microtubules thus altering the fungal
process of mitosis.

48. Therapeutic uses
 Infections that are readily treatable with this
agent include infections of the hair (tinea
capitis) ringworm of the glabrous skin; tinea
cruris and tinea corporis.
 Griseofulvin also is highly effective in
"athlete's foot".
 Griseofulvin has been largely replaced by
terbinafine for the treatment of dermatophytic
infections of the nails

49. Adverse effects
 Adverse effects include an allergic syndrome
much like serum sickness, hepatitis.
 Griseofulvin induces hepatic cytochrome P450
activity
 It also increases the rate of metabolism of a
number of drugs, including anticoagulants.
 Patients should not drink alcoholic beverages
during therapy, because griseofulvin
potentiates the intoxicating effects of alcohol.

50. Topical antifungals
Nystatin
 Nystatin is a polyene antibiotic, and its
structure, chemistry, mechanism of
action, and resistance resemble those of
amphotericin B.
 Some common indications include
oropharyngeal thrush, vaginal
candidiasis, and intertriginous candidal
infections

51.  Tolnaftate effective in treatment of most
cutaneous mycoses caused by
Trichophyton rubrum , T. tonsurans,
Microsporum gypseum M. canis,, but it is
ineffective against Candida
 Naftifine
Naftifine inhibit squalene epoxidase and
thus inhibit fungal biosynthesis of
ergosterol. It is effective for the topical
treatment of tinea cruris and tinea corporis;

52. Topical Azoles
 The two azoles most commonly used topically
are clotrimazole and miconazole.
Clotrimazole
 It is use for treatment of dermatophyte
infections ,cutaneous candidiasis ,vulvovaginal
candidiasis, oral and pharyngeal candidiasis .
 It may cause erythema, edema, vesication,
skin peeling, pruritus, and urticaria.

53. Miconazole
 It is used in treatment of tinea pedis, tinea
cruris, , vulvovaginal candidiasis
 Pruritus sometimes is relieved after a single
application.
 Some vaginal infections caused by Candida
glabrata also respond.
 Adverse effects from topical application to the
vagina include burning, itching, or irritation in
about 7% of recipients.

54.  Terconazole and Butoconazole is used
for vaginal candidiasis.
 Tioconazole is used for Candida
vulvovaginitis
 Oxiconazole, Sulconazole, and
Sertaconazole are used for topical
treatment of infections caused by the
common pathogenic dermatophytes.

55. Miscellaneous Antifungal Agents
Undecylenic Acid
 It is primarily fungistatic, although
fungicidal activity may be observed with
long exposure to high concentrations of
the agent .
 Undecylenic acid preparations are used in
the treatment of various dermatomycoses,
especially tinea pedis.

56. Benzoic Acid and Salicylic Acid
 An ointment containing benzoic and salicylic
acids is known as Whitfield's ointment.
 It combines fungistatic action of benzoate with
keratolytic action of salicylate.
 It contains benzoic acid and salicylic acid in a
ratio of 2:1 and is used mainly in treatment of
tinea pedis.
 Since benzoic acid is only fungistatic,
eradication of infection occurs only after
infected stratum corneum is shed, and
continuous medication is required for several
weeks to months.

57. Refernces
 Harvey,R.A and Champe,P.C. Lippincott’s
Pharmacology.4th edidtion.(2006)
 Katzung,B.G. and Masters,S.B.Basic and
clinical pharmacology 12th edition.(2012)
 Brunton.L, Chabner.B, and
Knollman.B.Goodman and Gillman’s The
Pharmacological Basis of Therapeutics.12th
eidtion.(2011)