Classification of antifungal drugs Six groups 1- Antibiotics [ Amphotricin B,(AMB), Nystatin, Greiofulvin] 2- Antimetabolities [ 5- Flucytosine,(5-FC), inhibition nucleic acid synthesis] 3- Azoles: a-Imidazoles: Bifonazole, Clotrimazole, Econazole, Ketoconazole, Miconazol. b- Triazoles: Fluconazole, Itraconazole, Voriconazole Inhibition of ergosterol synthesis. 4- Allylamine [Terbinafine, Naftifine ] Inhibition of Lanosterol and Ergosterol synthesis. 5- Echinocandins Inhibit fungal cell wall biosynthesis 6- Miscellaneous Antifungals [ Tolnaftant, Undecylenic acid, Benzoic acid, Ciclopirox olamine. ]

1. Antifungal Drugs
By
Dr. Saad Raheem

2. Types of fungal infections
1- Superficial : Affect skin – mucous membrane. e.g.
Tinea versicolor
Dermatophytes : Fungi that affect keratin layer of
skin, hair, nail. e.g. tinea pedis , ring worm infection
Candidiasis : Yeast-like, oral thrush, vulvo-vaginitis.

3. 2- Deep infections/ Systemic
Blastomyces
Coccidiodes
Cryptoccocus
Histoplasma
Sporotrichosis
While Systemic affected Internal organs like brain,
lung, GIT, liver, spleen, eye, etc.

4. Classification of antifungal drugs
Six groups
1- Antibiotics [ Amphotricin B,(AMB), Nystatin, Greiofulvin]
2- Antimetabolities [ 5- Flucytosine,(5-FC), inhibition
nucleic acid synthesis]
3- Azoles: a-Imidazoles: Bifonazole, Clotrimazole, Econazole,Imidazoles: Bifonazole, Clotrimazole, Econazole,
Ketoconazole, MiconazolKetoconazole, Miconazol..
b-b- Triazoles: Fluconazole, Itraconazole, VoriconazoleTriazoles: Fluconazole, Itraconazole, Voriconazole
Inhibition of ergosterol synthesis.Inhibition of ergosterol synthesis.

5. 4- Allylamine [Terbinafine, NaftifineTerbinafine, Naftifine ]]
Inhibition of Lanosterol and Ergosterol synthesis.Inhibition of Lanosterol and Ergosterol synthesis.
5-5- Echinocandins
Inhibit fungal cell wall biosynthesis
6-6- Miscellaneous Antifungals [ Tolnaftant, Undecylenic[ Tolnaftant, Undecylenic
acid, Benzoic acid, Ciclopirox olamine. ]acid, Benzoic acid, Ciclopirox olamine. ]

6. I. AntifI. Antifungalungalss damagingdamaging permeabilitypermeability
of the cell membraneof the cell membrane..
•Imidazoles: Bifonazole, Clotrimazole, Econazole,Imidazoles: Bifonazole, Clotrimazole, Econazole,
Ketoconazole, MiconazoleKetoconazole, Miconazole
•Triazoles: Fluconazole, Itraconazole, VoriconazoleTriazoles: Fluconazole, Itraconazole, Voriconazole
•AAllylaminellylaminess: Terbinafine, Naftifine: Terbinafine, Naftifine
•MorpholinMorpholineses: Amorolfine: Amorolfine
•Thiocarbamates: Tolciclate, TolnaftateThiocarbamates: Tolciclate, Tolnaftate
•Substituted pyridones: CiclopiroxSubstituted pyridones: Ciclopirox
•PPolyene antibiotics: Amphotericin B, Nystatinolyene antibiotics: Amphotericin B, Nystatin
II.II. Antifungals inhibiting chitin synthesis in the cell wallAntifungals inhibiting chitin synthesis in the cell wall..
CaspofunginCaspofungin
III.III. Antifungals inhibiting synthesis of nucleic acidsAntifungals inhibiting synthesis of nucleic acids
FlucytosineFlucytosine

8. Classification According to Route of
Administration
Systemic :
Griseofulvin , Amphotericin- B , Ketoconazole ,
Fluconazole , Terbinafine.
Topical
In candidiasis :
Imidazoles : Ketoconazole , Miconazole.
Triazoles : Terconazole.
Polyene macrolides : Nystatin
Gentian violet : Has antifungal & antibacterial.

9. In Dermatophytes :
Squalene epoxidase inhibitors : Terbinafine &
Naftifine.
Tolnaftate.
White field ointment : 12% Benzoic acid & 6%
Salicylic acid .
Castellani paint.

10. Antifungal Agents
1. Polyene Antifungal Drugs
These drugs interact with ergosterol in the fungal cell membrane and form
pores
Polyenes are related chemically to the macrolide antibiotics with the large
lactone ring but have the distinctive characteristic of conjugated double
bonds and a lipophilic (a chromophore of 4-7 conjugated double bonds) and
hydrophilic side (several alcohols, acids and usually a sugar).
The number of conjugated double bonds correlates directly with antifungal
activity in vitro and inversely with the degree of toxicity to mammalian
cells.
They are unstable, only slightly soluble, and poorly absorbed when taken
orally.
•Amphotericin B
•Nystatin
• (Natamycin) Pimaricin

11. Mechanism of Action of Polyenes

13. Amphotericin B, a polyene
antibiotic, is produced by
Streptomyces nodosus. Discovered
in 1956 has been for 30 years the
main available drug to control
serious fungal infections. Amp. B
is indicated for treatment of
severe, potentially life threatening
fungal infections.
Unfortunately, it must be given IV and is toxic (due to nonselective
action on cholesterol in mammalian cell membranes).
Resistance is due to lower production of membrane sterols or altered
sterols, but is relatively rare at present. Target modification and
reduced access to target are other mechanisms of resistance.
Amphotericin B

14. Amphotericin B
Disposition
Amp. B deoxycholate ( Fungizone ) is not absorbed orally. It is
given by slow IV infusion. It is highly bound to cholesterol-
lipoprotein and has a plasma T1/2 of about 1 day and 1-2 weeks
from tissues. It is excreted in urine over a long time.
Penetration into the CNS is poor. However, for fungal
infections of the CNS, amphotericin B is mixed with
cerebrospinal fluid (CSF) that is obtained from a spinal tap.
The solution of amphotericin is then reinjected through the tap.

15. Products:
Amphotericin B. (Fungizone ®) 50 mg/vial with 41mg of sodium deoxycholate.
Reconstitute with water. Give a test dose and gradually increase dose. Don't
exceed 1.5mg/kg/d. Alternate day therapy is sometimes used. Several months
of therapy is usually needed.
Abelcet (Liposome Co.) 1:1 mixture of amphotericin and lipid complex, 100
mg/20 ml. Rationale for this lipid preparation is that amphotericin B should
have a greater affinity for the lipid vehicle than for cholesterol in cell
membranes, thus lower toxicity. Lipid associated amphotericin B is drawn into
the reticuloendothelial system, concentrating in lymphatic tissues, spleen, liver
and lungs where infectious fungi concentrate. Lipases excreted from fungi
release drug from lipid carrier allowing to bind to ergosterol in fungal cell
membranes to exert fungistatic and fungicidal activities.
Aphotec (Sequus Pharmaceuticals) cholesteryl colloidal dispersion, 50 or 100
mg/20 ml. Supplied in variety of topical forms including a 3% cream, lotion or
ointment and 100mg/mL oral suspension to treat cutaneous and
mucocutaneous mycoses caused by Candida albicans
AmBiosome (Fujisawa) liposomal, 50mg/vial.

16. Amphotericin B
Adverse Effects:
Reactions on infusion - headache, fever, chills, anorexia, vomiting, muscle and joint
pain. Pain at site of injection and thrombophlebitis are frequent complications of
intravenous administration. Drug must never be given intramuscular. Can give
aspirin, meperidine, steroids, antiemetics etc to prevent some of these.
Nephrotoxicity - chronic renal toxicity in up to 80% of patients taking the drug for
prolonged periods. It is reversible but can be irreversible in high doses. Test for
kidney function regularly. This is the most common limiting toxicity of the drug.
Hematologic - hemolytic anemia due to effects on RBC membrane.
Other less common reactions - cardiac, convulsions, neuropathy, hearing loss,
allergic, etc.
Some decrease in adverse effects particularly nephrotoxicity with liposomal
preparations; the idea with the lipid preps is to decrease nonspecific binding to
mammalian membranes.

17. Nystatin
Isolated from streptomyces noursei in
1951. A conjugated tetraene, is the first
clinically useful polyene antifungal
antibiotic. Available in oral tablets,
powder for suspension, vaginal tablets,
pastilles. This polyene is used for local
therapy only (not absorbed).
Nystatin
No significant adverse effects with these uses. Combined with
tetracycline to prevent monilial overgrowth caused by the
destruction of bacterial microflora of the intestine during
tetracycline therapy.
(Mycostatin ® and other generic products)

18. Natamycin (Pimaricin; Natacyn)
Polyene antibiotic obtained from cultures of Streptomyces natalensis.
Structures consists of 26-membered lactone instead of the 38 for Nystatin
and Amphotericin B. The 26-membered polyenes cause both K leakage
and cell lysis at same concentration.
Natamycine supplied as a 5% ophthalmic suspension intended for the
treatment of fungal conjunctivitis, blepharitis and keratitis.
Natamycin
O
OH NH2
OH
CH3
O
HOOC
OH
OHO
OH
O
O
O
H3C
Natamycin

19. Griseofulvin
Antifungal antibiotic produced from Penicillium griseofulvin. Effects
on microtubules to inhibit cell division . Inhibits fungal mitosis by
interfering with microtubule function, distrupts mitotic spindle during
metaphse ( metaphse arrest ).
Therapy must continue until new tissue replaces old diseased tissue.
When given orally, plasma-borne griseofulvin becomes incorporated
into keratin precursor cells and ultimately into keratin which cannot then
support fungal growth.

20. Griseofulvin(cont.)
 Used to treat dermatophyte infections ( ring worm of skin, hair,
nails ).
 Ineffective topically.
 Not effective in subcutaneous or deep mycosis.
 Fungistatic, has a narrow spectrum.
 Present as microsize and ultramicrosize
 Given orally (Absorption increases with fatty meal )
 Half-life 24 hours
 Taken selectively by newly formed skin & concentrated in the keratin.
 Induces cytochrome P450 enzymes
 Should be given for 6-8weeks for skin & hair infections to allow
replacement of infected keratin by the resistant structure.
 Is category – c – in pregnancy.

21. DOSAGE AND ADMINISTRATION
Adults: Daily administration of 375 mg (as a single dose or in divided doses) will give a
satisfactory response in most patients with tinea corporis, tinea cruris, and tinea capitis.
For those fungal infections more difficult to eradicate, such as tinea pedis and tinea
unguium, a divided dose of 750 mg is recommended.
Pediatric Use: Approximately 7.3 mg per kg of body weight per day of ultramicrosize
griseofulvin is an effective dose for most pediatric patients. On this basis, the following
dosage schedule is suggested: 16-27 kg: 125 mg to 187.5 mg daily. over 27 kg: 187.5 mg to
375 mg daily. Children and infants 2 years of age and younger - dosage has not been
established. So from 20 – 25 mg per kg per day ( microsize ) or 15 – 20 mg per kg per day (
ultramicrosize ).
Clinical experience with griseofulvin in children with tinea capitis indicates that a single
daily dose is effective. Clinical relapse will occur if the medication is not continued until
the infecting organism is eradicated.

22. Griseofulvin
Adverse effects:
Headache is a common adverse effect. May cause aplastic
anemia.
Peripheral neuritis, mental confusion, fatigue, vertigo, GIT
upset,enzyme inducer, blurred vision, allergic reaction,
photosensitivity, angioedema.
Being an antimiototic-bone marrow suppression, leucopenia,
neutropenia.
Increases alcohol intoxication.

23. 2-Allylamine (Terbinafine)
The drug is primarily a fungicidal agent and highly active against
dermatophytes, but less active against molds, dimorphic fungi,
and various yeasts. Drug of choice for treating dermatophytes
(onychomycoses).
 Terbinafine inhibits the enzyme squalene epoxidase in the fungal
cell membrane, thereby blocking the biosynthesis of ergosterol.
(Squalene epoxidase, a complex, microsomal non-cytochrome P450
enzyme, catalyzes the first enzymatic step of ergosterol synthesis:
the conversion of squalene into squalene epoxide). Consequently,
terbinafine causes an abnormal intracellular accumulation of
squalene and a deficiency in ergosterol.
(Accumulation of squalene ,which is toxic to the organism causing
death of fungal cell).

25. Fungicidal , its activity is limited to candida albicans &
dermatophytes.
Effective for treatment of onychomycoses
6 weeks for finger nail infection & 12 weeks for toe nail infections .
Terbinafine is well absorbed from the gastrointestinal tract,
mostly in chylomicrons. The distribution half-life is 1.5 hours, and
the elimination half-life is approximately 22 hours.Terbinafine is
highly lipophilic and keratophilic in nature and, therefore, is
widely distributed.
upon absorption throughout skin and adipose tissue. Terbinafine
is extensively biotransformed by the liver, mostly through
oxidation by a very small fraction of P450 isoenzymes. More than 80
percent of the drug is excreted in urine; the rest is eliminated with
feces.

26. Side Effect & Contraindication
Highly protein binding
Accumulates in skin , nails, fat.
Severely hepatotoxic, liver failure even death.
Accumulate in breast milk , should not be given to nursing
mother.
GIT upset (diarrhea, dyspepsia, nausea )
Taste & visual disturbance.
 Terbinafine is a pregnancy category B.

27. Dosage Schedules and Formulations
Terbinafine is supplied as a 250-mg tablet and should be
taken once daily for all regimens except twice-daily pulse
dosing.
Table for treatment schedules.

28. TABLE Terbinafine Dosing Regimen

29. 3-Azole Antifungal Agents
Azole antifungal agents are the largest class of synthetic antimycotics.
About 20 agents on the market today. Some used topically to treat
superficial dermatophytic and yeast infections. Others used systemically to
treat severe fungal infections. Antifungal activity stems from the presence
of an aromatic five member heterocyclic, either an imidazole (two nitrogen
atoms) or a triazole (three nitrogen atoms)
The first members of the class were highly substituted imidazoles (clotrimazole,
miconazole) were not absorbed orally. Ketoconazole introduced in 1984 was the
first effective oral therapy for Candida.
Itroconazole and Fluconazole are more potent, less toxic and provide effective oral
therapy for many systemic fungal infections. These two are triazoles.
Another triazole has been recently introduced (voriconazole).

30. N
N
CH2
HC
R
Cl
Cl
MiconazoleR =
Cl
ClCH2O
ClCH2O Econazole
Oxiconazole
ClCH2S Sulconazole
S
Cl
CH2O Tioconazole
N O
Cl
CH2 Cl
NNCCH3
O
O CH2
N
N
CH2
O
O
Cl
Cl
Ketoconazole
N
N
N NN
CHCH3CH2
CH3
O
O CH2
N
N
N
CH2
O
O
Cl
Cl
Itraconazole
N
N
N
CH2
N
N
N CH2
F
F
OH
Fluconazole
CH
F
F
OH
N
N
CH3
F
N
N
N
CH2
Voriconazole
Examples of Azole agents

31. A- Imidazoles
Broad class of antifungal. Impede synthesis of a componentof the
fungal cell wall through inhibition of Lanosterol 14α demthylase
Ketoconazole
Miconazole
Clotrimazole
They lack selectivity ,they inhibit human gonadal and
steroid synthesis leading to decrease testosterone & cortisol
production.
Also, inhibit human P-450 hepatic enzyme.

32. Ketoconazole
 Well absorbed orally .
 Bioavailability is decreased with antacids, H2 blockers , proton pump
inhibitors & food .
 Cola drinks improve absorption in patients with achlorhydria.
 Half-life increases with the dose , it is (7-8 hrs).
 Inactivated in liver & excreted in bile (feces ) & urine.
 Does not cross BBB.
Clinical uses:
Used topically or systematic (oral route only ) to treat :
 1- Oral & vaginal candidiasis.
 2- Dermatophytosis.
 3- Systemic mycoses & mucocutaneous candidiasis.

33. Adverse Effects
Nausea, vomiting ,anorexia
Hepatotoxic
Inhibits human P 450 enzymes
Inhibits adrenal & gonadal steroids leading to :
Menstrual irregularities
Loss of libido
Impotence
Gynaecomastia in males
Contraindications & Drug interactions:
Prgnancy, lactation ,hepatic dysfunction
Interact with enzyme inhibitors , enzyme inducers.
H2 blockers & antacids decrease its absorption

34. B-Triazoles
Itraconazole
Fluconazole
Voriconazole
They are :
Selective
Resistant to degradation
Causing less endocrine disturbance

35. Itraconazole
 Lacks endocrine side effects
 Has a broad spectrum activity
 Given orally & IV
 Food increases its absorption
 Metabolized in liver to active metabolite
 Highly lipid soluble ,well distributed to bone, sputum ,adipose
tissues.
 Can not cross BBB. Half-life 30-40 hours
 Used orally in dermatophytosis & vulvo-vaginal candidiasis.
 IV only in serious infections.
 Effective in AIDS-associated histoplasmosis
Side effects :
 Nausea, vomiting, hypokalemia, hypertension, edema, inhibits the
metabolism of many drugs as oral anticoagulants.

36. Onychomycosi
s
Tinea capitis
Tinea corporis,
tinea cruris,
tinea pedis
ADULT PEDIATRIC
Fingernails: 200 mg bid × 1
wk/mo × 2 pulses
Toenails: 200 mg/day × 12
wk
or
200 mg bid × 1 wk/mo × 3
pulses
250mg/day × 2-8 wk
200mg bid × 1 wk
or
100-200 mg/day × 2-4 wk
Fingernails: 5 mg/kg/day ×
1 wk/mo × 2 pulses
Toenails: 5 mg/kg/day × 1
wk/mo pulsed × 3 pulses
Trichophyton infections:
5mg/kg/day × 2-4 wk
Microsporum infections:
5mg/kg/day × 4-8 wk
Dose by weight × 1-4 wk
TABLE Itraconazole Dosing Regimen

37. Oropharyngeal
candidiasis
Pityriasis versicolor
ADULT PEDIATRIC
Swallow solution 100-200
mg/day
200mg/day × 5-7 days,
prevent recurrence with
200 mg bid once/mo
Swallow solution by
weight
Cont…

38. Fluconazole
 Water soluble
 Completely absorbed from GIT
 Excellent bioavailability after oral administration
 Bioavailability is not affected by food or gastric PH
 Conc. in plasma is same by oral or IV route
 Has the least effect on hepatic microsomal enzymes.
 Drug interactions are less common
 Penetrates well BBB so, it is the drug of choice of cryptococcal
meningitis
 Safely given in patients receiving bone marrow transplants (reducing
fungal infections)
 Excreted mainly through kidney
 Half-life 25-30 hours
 Resistance is not a problem

39. Clinical uses
Candidiasis
( is effective in all forms of mucocutaneous candidiasis)
Cryptococcus meningitis
Histoplasmosis,
blastomycosis, , ring worm.
Not effective in aspergillosis

40. Side effects
Nausea, vomiting, headache, skin rash , diarrhea,
abdominal pain , reversible alopecia.
Hepatic failure may lead to death
Highly teratogenic ( as other azoles)
Inhibit P450 cytochrome
No endocrine side effects

41. New azole agent more recently approved
Posaconazole
Novel trizole antifungal recently approved for use as an oral
suspension to treat invasive fungal infections. Fungistatic against
Candida and fungicidal against Asperigillus species.
Similar structure to Itraconazole, absorbtion greatly affected by
food. Mainly metabolized by phase II glucuronide conjugation
and has little interaction with P450 enzymes.
Posoconazole

42. 4- Nucleoside Antifungals
Orally active antifungal with a very narrow spectrum of activity
Flucytosine was synthesized in 1957 as an antitumor agent. It was inactive but
it was found to have antifungal activity. Drug inters fungal cell through active
transport on ATPases that normally transport pyrimidines. Once inside cells,
fungal cytosine deaminase convert the drug to active 5-fluorouracl (5FU) which is
incorporated into RNA causing faulty RNA synthesis. It is also is a strong, non-
competitive inhibitor of thymidylate synthesis interrupting the one carbon pool
substrate. Mammalian cells do not contain cytosine deaminase.
N
N
H
O
NH2
F cytidine
deaminase
Flucytosine
N
N
H
O
F
OH
5-Fluorouracil
Flucytosine (5-Fluorocytosine )

43. Resistance develops rapidly and occurs on many levels e.g. transport into the
cell and cytosine deaminase steps. After a few dosing intervals the drug is
essentially useless. To avoid rapid resistance, combination with
Amphotericin B, and the combination is synergistic. It is also synergistic
with itraconazole and fluconazole, and interest in these combinations for
treatment of systemic Candida infections is increasing. Amphotericin B
damaged membranes are thought to allow better entry of flucytosine.
Used (with Amp. B) for Cryptococcal meningitis, systemic Candida
infections, and some other systemic fungal infections.
Adverse Effects
1)GI upset - very common.
2)Hepatic - 5% have increased transaminases.
3)Hematologic - anemia, leukopenia, thrombocytopenia; this is the major
complication of therapy and may be due to low levels of 5-FU circulating.
4)adverse effects seen when plasma levels reach >100 mcg/ml
Nucleoside Antifungals

44. 5- Cell wall inhibitors
Echinocandins, a group of cyclic peptides with long lipophillic
sidechains have been under investigation for a number of years. They
interfere with cell wall biosynthesis through inhibition of the enzyme β-
1,3-glucan synthase. Reduction of in the glucan content weakens the cell
wall and leads to rupture of fungal cells.

45. Echinocandins
Micafungin
Caspofungin
(parenteral)
Anidulafungin
approved for invasive
aspergillosis in patients
refractory to or
intolerant of other
therapies . IV use only

46. Caspofungin
Inhibits the synthesis of fungal cell wall by inhibiting the
synthesis of β(1,3)-D-glucan, leading to lysis & cell death.
Given by IV route only
Highly bound to plasma proteins
Half-life 9-11 hours
Slowly metabolized by hydrolysis & N-acetylation.
Elimination is nearly equal between the urinary & fecal
routes.

47. Undecylenic Acid
H2C=CH(CH2)8COOH
Widely used as the zinc salt in OTC preparations for topical treatment of
infections by dermatophytes. A fungistatic acting through non-specific
interaction with components in cell membrane.
Can be used in concentrations up to 10% in solution, powder and emulsions.
Traditionally used for athlete’s foot (tinea pedis) although cure rates are low.
Ciclopirox Olamine
A hydroxylated pyridinone used for superficial
dermatophytic infections mainly onychomycosis. It
caused inhibition of polyvalent cations (Fe+3) and
caused inhibition of metallic enzymes in the fungal
cell this distrupt cellular function lead to demise of
the fungus. A new formulation of an 8% lacquer
has been recently introduced for treating nail
infections. Ciclopirox
6- Miscellaneous Antifungals