CLASSIFICATION OF ANTIFUNGALS, MECHANISMS OF ACTION OF ANTIFUNGALS, TOPICAL ANTIFUNGAL AGENTS, SYSTEMIC ANTIFUNGAL AGENTS

3. • Fungi are eukaryotic, heterotrophic organisms that live as
saprobes or parasites.
• Complex organisms in comparison to bacteria.
• Have nucleus and well defined nuclear membrane, and
chromosomes.
• Have rigid cell wall composed of chitin (bacterial cell wall is
composed of peptidoglycan).
• Fungal cell membrane contains ergosterol (human cell
membrane is composed of cholesterol).
• Antibacterial agents are not effective against fungi.

4. • Superficial dermatophytoses usually respond to
topical antifungal agents which rarely have serious
side effects.
• Fungal infections of the hair and nails as well as
systemic mycoses, immunocompromised or who
have extensive skin involvement generally
necessitate treatment with systemic antifungal
medications.

10. I. Antifungals inhibiting synthesis of THE CELL WALL
II. Antifungals altering PERMEABILITY OF THE CELL
MEMBRANE
III.Antifungals disrupt MICROTUBULE FUNCTION 
Inhibit mitosis
IV.Antifungals inhibiting synthesis of THE NUCLEIC
ACIDS

12. DRUG CLASS AGENTS
IMIDAZOLES
Clotrimazole
Econazole
Ketoconazole
Miconazole
Oxiconazole
Sertaconazole
Terconazole
Tioconazole
Butoconazole
Sulconazole
ALLYLAMINES Terbinafine Naftifine
BENZYLAMINE Butenafine
THIOCARBAMATES Tolnaftate Tolciclate
POLYENES* Nystatin* Amphotericin B*
HYDROXYPYRIDONE Ciclopirox olamine
OTHERS
Whitfield's ointment
Selenium sulfide
Undecylenic acid
Iodoquinol
Clioquinol

25. 1. DERMATOPHYTE infections such as tinea corporis, tinea
cruris, tinea faciei, tinea manuum, tinea pedis.
2. As an ADJUNCT to oral therapy for tinea capitis, tinea
barbae and onychomycosis.
3. YEAST infections; mucocutaneous candidiasis, pityriasis
versicolor.
4. SEBORRHEIC DERMATITIS; Ketoconazole, selenium sulfide &
ciclopirox olamine.
5. MOULD skin infections such as tinea nigra.

26. I. Skin: cream, gel, ointment, lotion, solution, powder,
aerosol solution, aerosol powder, aerosol foam.
II. Hair: shampoo, gel, lotion, solution.
III. Nail: nail lacquer, nail solution.
IV. Oral mucosa: oral drops, oral gel, troches, lozenges.
V. Vaginal mucosa: cream, vaginal suppositories,
vaginal tablets.

30. DRUG CLASS MECHANISMS OF ACTION
IMIDAZOLES
• Inhibition of fungal cytochrome P450-dependent 14-α-demethylase 
prevents synthesis of ergosterol  Interfere with CM synthesis.
• Most azoles are fungistatic, some are fungicidal at high concentration.
• Also inhibit neutrophil chemotaxis, calmodulin activity, synthesis of
leukotrienes & prostaglandins, and histamine release from mast cells.
ALLYLAMINES
BENZYLAMINE
THIOCARBAMATES
• Inhibition of squalene epoxidase  accumulation of intracellular squalene
(fungicidal)  Interfere with CM synthesis.
• Have both fungistatic and fungicidal effects.
POLYENES
• Bind irreversibly to ergosterol  pore in CM   CM permeability.
• Fungistatic at low concentrations & fungicidal at high concentration.
HYDROXY-
PYRIDONE
• Chelates polyvalent cations (e.g. Fe3+) that have important functions in
fungal cytochromes, catalases and peroxidases; it thereby inhibits
respiration, blocks transport of amino acids & alters CM permeability.
• Active against dermatophytes, Malassezia spp., Candida, actinomycetes,
molds, and Gram-positive & Gram-negative bacteria.
SELENIUM
SULFIDE
• Antimitotic properties; reduces cellular adhesion in the stratum corneum,
facilitating shedding of fungi.

31. • The creams are applied to the affected area twice daily for
two to four weeks, including a margin of several
centimetres of normal skin.
• Continue for one or two weeks after the last visible rash has
cleared. Repeated treatment is often necessary.
• Shampoos are used every 3 to 4 days and are left in place
for 5 minutes before rinsing.
• Nystatin oral suspension is held in the mouth for as long as
possible before swallowing or expectorating repeated 4
times/d.

32. • The most common is LOCAL SKIN IRRITATION, which may be
more severe with occlusion.
• Clinical manifestations include burning, stinging, pruritus,
erythema, edema, peeling, blistering and allergic contact
dermatitis.
• Clioquinol can cause discoloration of clothes, skin, hair and
nails.

34. I. Antifungals inhibiting synthesis of THE CELL WALL
– Caspofungin
II. Antifungals altering PERMEABILITY OF THE CELL MEMBRANE
1. Polyenes
2. Azoles
3. Allylamines
III. Antifungals disrupt MICROTUBULE FUNCTION  Inhibit mitosis
– Griseofulvin
IV.Antifungals inhibiting synthesis of THE NUCLEIC ACIDS
– Flucytosine

35. MAY BE REQUIRED FOR A FUNGAL INFECTION IF:
1. It is extensive or severe.
2. It resists topical antifungal therapy.
3. It affects hair-bearing areas (tinea capitis and tinea
barbae) or nails.

37. • Amphotericin B and Nystatin interacts with ergosterols, forms
pores that increase membrane permeability and allow leakage
of intracellular ions & macromolecules from fungal cell  cell
death.
• Amphotericin has a lesser affinity for the mammalian cell
membrane component cholesterol, but this interaction does
account for most adverse toxic effects.
• Too toxic for systemic use, nystatin is limited to the topical
treatment of superficial infections caused by C. albicans.

39. • Antifungal agent with the broadest spectrum of activity
• Drug of choice for the vast majority of life-threatening
systemic fungal infections.
• Intrathecal infusion of amphotericin B is useful in patients
with meningitis caused by Coccidioides.

41. • Griseofulvin is an oral fungistatic agent available since 1958
used in the long-term treatment of dermatophyte infections
caused by Epidermophyton, Microsporum, and Trichophyton
spp.
• Produced by the mould, Penicillium griseofulvum.
• It is not effective against yeasts such as candida or malassezia.
• Griseofulvin may still be preferable for tinea capitis, especially
when due to Microsporum canis infection, and is generally well
tolerated in children.
• It has been withdrawn from the market in many countries, as it
has been superceded by more effective and safer antifungal
drugs.

43. MOA:
• It inhibits fungal growth by binding to the
microtubules responsible for mitotic spindle
formation.
• Interacting with microtubules  disrupts
mitotic spindle  inhibiting mitosis.
• The drug binds to keratin precursor cells and
newly synthesized keratin in the stratum
corneum of the skin, hair, and nails, stopping
the progression of dermatophyte infection.

44. ADME:
• They should be taken after a fatty meal or drink of milk as fat
increases the absorption. Drug particle size reduction through
micronization and ultra-micronization has also significantly
enhanced oral absorption.
• It is carried into the skin by sweat and within a couple of weeks is
concentrated in the outer skin layers.
• Eliminated in urine and faeces.
• It is quickly cleared from skin and hair when it is stopped so
treatment should be continued until clinical cure.

45. USES & DOSAGES:
• Dermatophytosis only.
• Can be taken once daily.
• Adults: 500 mg to 1 g /day.
• Children: 10-25 mg/kg/day.
• Duration of treatment;
– 2–4 weeks for tinea corporis
– 4–8 weeks for tinea pedis
– 6–12 weeks for tinea capitis
– 4 months for tinea unguium of fingernail
– 6 months for tinea unguium of toenail or until all signs of nail
infection have gone.

46. SIDE EFFECTS:
1. Gastrointestinal disturbances: nausea, vomiting, heartburn, cramps, flatulence, taste
disturbance.
2. Central nervous system disturbances: Headaches (most common as well as
gastrointestinal upsets), visual disturbance, dizziness, depression, nightmares, insomnia.
fever.
3. Liver affection: Hepatotoxicity.
4. Allergic reactions: including urticaria, fixed drug eruption, exfoliative dermatitis, lupus
erythematosus and photosensitivity.
5. Urinary disturbance: frequency, enuresis.
6. Sore throat.
7. Menstrual disturbance.
8. Can precipitate or exacerbate porphyria.

47. Griseofulvin Side Effects Mnemonic
Do Dizziness | Depression
U Urinary disturbances
Have Headaches | Hepatotoxicity
G Gastrointestinal disturbances
R Reactions
I Insomnia
S Sore throat
E Exfoliative dermatitis
O ------
F Fever | Fixed drug eruption
U Urticaria
L Lupus erythematosus
V Visual disturbance
I ------
N Nervous system disturbances | Nightmares
Pills Photosensitivity | Porphyria
Mammy? Menstrual disturbance

48. CONTRAINDICATIONS:
1. Porphyrias
2. Liver failure
3. Pregnancy as there is a slight risk of malformation of the
fetus.

49. DRUG INTERACTIONS:
1. Griseofulvin interacts with alcohol and can induce a disulfiram-like
reaction and can cause severe nausea and vomiting.
2. Griseofulvin can cause an increase in a liver enzyme reducing the
concentration of:
i. Warfarin
ii. Oral contraceptive (increasing the chance of pregnancy)
iii. Salicylates

51. • They are synthetic drugs with broad-
spectrum fungistatic activity. Azoles
can be divided into two groups:
A. IMIDAZOLES (azole nucleus
contains 2 nitrogen atoms): older
agents Ketoconazole, Miconazole,
Econazole, Clotrimazole…….
B. TRIAZOLES (azole nucleus contains
3 nitrogen atoms): newer agents
Itraconazole, Fluconazol, Vorionazole
→ systemic treatment

52. MOA:
• Inhibition of fungal cytochrome P450-dependent 14-α-
demethylase  prevents synthesis of ergosterol  Reduced
fungal membrane ergosterol concentrations result in
damaged, leaky cell membranes.
• The toxicity of these drugs depends on their relative affinities
for mammalian and fungal cytochrome P450 enzymes.

54. • Contain 2 Nitrogen atoms attached to the ring.
• Reduce the formation of ergosterol in the cell membrane. which
become permeable to cellular constituents.
• They lack selectivity, and also inhibits human gonadal and steroid
synthesis leading to decreased testosterone and cortisol production.
• Agents:
– Ketoconazole
– Miconazole
– Clotrimazole
– Isoconazole
– Tioconazole……….

57. • It is imidazole antifungal agent taken orally.
• Epigastric distress can be reduced by taking ketoconazole with
food.
• It remains useful in the treatment of cutaneous and mucous
membrane dermatophyte and yeast infections, but it has been
replaced by the newer triazoles in the treatment of most
serious Candida infections and disseminated mycoses.
• Ketoconazole is usually effective in the treatment of thrush, but
fluconazole is superior to ketoconazole for refractory thrush.
• Not used in pregnancy, lactation, hepatic dysfunction.

58. ADME:
• Well absorbed orally as acidic environment favors its dissolution.
• Ketoconazole and itraconazole may not be absorbed in patients with
achlorhydria. Cola drinks improve its absorption in patients with
achlorhydria.
• Bioavailability is impaired with food.
• 84% is bound to plasma proteins.
• Metabolized extensively in liver and inactive products appear in the
feces.
• Moderate hepatic dysfunction has no effect on drug concentration.
• It does not enter CSF.

59. FORMULATION:
• Available in 200 mg tablets.

60. USES & DOSAGES:
• Effective against most dermatophytes, Candida spp.
• Used via oral route only to treat;
1. Superficial fungal infections: widespread, severe or resistant to topical antifungals
– Oral & vaginal candidiasis: 200 mg once-daily for 5 days
– Pityriasis versicolor: 200 mg once-daily for 5 days
– Dermatophytosis;
• In adults is 200 to 400 mg daily, taken for two to eight weeks. Nail infections are treated for up to
twelve months.
• The dose in children is usually 50 mg per day for those weighing less than 20 kg and 100 mg daily for
those 20-40 kg.
2. Systemic fungal infections:
– Histoplasmosis, non-meningeal cryptococcosis, Blastomycosis.

61. SIDE EFFECTS:
1. Gastrointestinal disturbances: Nausea, vomiting, anorexia, abdominal pain (dose
dependent).
2. Central nervous system disturbances.
3. Liver affection: Idiosyncratic hepatotoxicity (rare) - but may prove fatal. Liver enzyme
elevations during therapy are usually reversible.
4. Allergic reactions: Anaphylaxis, urticaria, pruritus.
5. Alopecia.
6. At higher doses, suppresses synthesis of adrenal gonadal steroids testosterone and cortisol
which leads to menstrual irregularities in women, loss of libido, impotence, reduced sperm
count and gynaecomastia in males. These hormonal effects have led to the use of
ketoconazole as a potential adjunctive treatment for prostatic carcinoma.

62. • Decrease in the
ergosterol in the
fungal membrane
by ketoconazole
reduces the
fungicidal action
of amphotericin

63. • In August 2013, the FDA announced that clinicians should no
longer prescribe ketoconazole (Nizoral) tablets as a first-line
therapy for any fungal infection, including Candida and
dermatophyte infections, because of the risk for severe liver
injury, adrenal insufficiency, and adverse drug interactions.
• Ketoconazole tablets were also withdrawn from the market in
the European Union in July 2013.

64. • They are more selective i.e. higher affinity to fungal enzyme.
• Penetrate to CNS.
• Resistant to degradation.
• Cause less endocrine disturbance.
• They tend to have fewer side effects, better absorption, better drug
distribution in body tissues, and fewer drug interactions.
• Main Agents:
1. Itraconazole
2. Fluconazole
3. Voriconazole

66. • It is a synthetic broad spectrum triazole.
• Administered orally as well as IV.
• Food increases its absorption.
• Requires a gastric pH for absorption may not be absorbed in patients
with achlorhydria.
• Highly lipid soluble, and water insoluble.
• Oral bioavailability is variable (20 to 60%).
• Lacks endocrine side effects of ketoconazole.

67. FORMULATIONS:
1. Capsules 100 mg should be taken with a full
meal to enhance absorption.
2. Oral solution 10 mg/ml should be taken on
an empty stomach as oral solution is 60%
more bioavailable than the capsules.
Pediatric dosing is 5 mg/kg daily.
3. Intravenous infusion, given 200 mg
intravenously twice a day for four doses and
then 200 mg every day.

68. ADME:
• Food increases its absorption.
• Absorption is improved by acid may be taken with orange juice or cola.
• It is highly protein bound (99%) and is metabolized in the liver and excreted into
the bile.
• It is highly lipid soluble and well distributed to skin, sebum, bone, sputum and
adipose tissue & to less extent sweat.
• Half life is 1-1.5 d.
• Does not penetrate into CSF adequately.
• The capsule is better absorbed with food, but the oral solution is better absorbed in
the fasting state.
• Therapeutic levels in the skin persist for 2-4 w after last dose.

69. USES & DOSAGES :
• Effective against dermatophytes, yeasts some molds.
I. Superficial fungal infections: widespread, severe or resistant to topical antifungals. 200 to 400
mg/day. Doses exceeding 200 mg/day are given in 2 divided doses
– Pityriasis versicolor: 200 mg daily for 5-7 days.
– Tinea corporis, tinea cruris: 100 mg daily for 2 w or 200 mg daily for 1 w.
– Tinea pedis, tinea manuum: 100 mg daily for 2-4 weeks OR 200 mg twice daily for one week.
– Tinea capitis: 5 mg/kg/d for 2 to 4 weeks or as 1- to 3-week-long pulses.
– Onychomycosis: 200 mg/day for 1.5-2 months (fingernails) or 3-4 months (toenails), OR 200 mg twice daily for 7 days,
repeated monthly for 2 months (fingernails) or 3-4 months (toenails).
– Vulvo-vaginal candidiasis: 200 mg twice for one day.
– Oropharyngeal and esophageal candidiasis (solution): Taken fasting in a dose of 100-200 mg once daily and swished
vigorously for few seconds in the mouth before swallowing to optimize topical effect for 1–3 weeks should be
continued for at least 2 weeks after symptoms resolve.
II. Systemic fungal infections: Blastomycosis, sporotrichosis, histoplasmosis and aspergillosis
– It can safely be administered prophylactically in patients receiving bone marrow transplants.

70. SIDE EFFECTS:
1. Gastrointestinal disturbances: anorexia,
nausea, vomiting, abdominal pain Relative to
capsules, the oral solution of itraconazole
more frequently causes diarrhea, abdominal
cramps, anorexia, and nausea.
2. Central nervous system disturbances:
fatigue, headaches, dizziness.
3. Liver affection: Hepatic dysfunction and
death. Elevated serum aminotransferases
hypertriglyceridemia if symptoms of
hepatotoxicity occur, the drug should be
discontinued and liver function assessed.
4. Allergic reactions: Morbilliform eruption,
pruritus, urticaria, Stevens–Johnson
syndrome (rarely), infusion site reactions in
parenteral administration.
5. Alopecia.
6. Fever.
7. Lower limb edema.
8. Hypokalemia.

72. • It is a synthetic broad spectrum triazole.
• It is relatively hydrophilic compared to other systemic azole
antifungal drugs.
• It is not affected gastric acidity.
• C. krusei is fluconazole-resistant.

73. ADME
• Bioavailability not altered by food or gastric acidity. Does not require an acidic
environment, as does ketoconazole and itraconazole for GI absorption.
• Excellent bioavailability by oral route (about 80 to 90% of an orally administered dose
is absorbed, yielding high serum drug levels).
• The t ½ of the drug is 1-1.5 d, permitting once-daily dosing in patients with normal
renal function. Only 10% of the circulating drug is bound to plasma proteins.
• The drug penetrates widely into most body tissues. Readily diffuses into body fluids,
including breast milk, sputum, saliva, and CSF.
• About 80% of the drug is excreted unchanged in the urine. Dosage reductions are
required in the presence of renal insufficiency.

74. FORMULATIONS:
• Capsules for oral administration 50 or 150 mg.
• Powder for oral suspension 50 mg/5ml
• Intravenous solutions containing 2 mg/ml.

75. USES & DOSAGES:
1. Superficial fungal infections:
– Pityriasis versicolor: 300 mg once weekly for 2 weeks.
– Candidiasis: very effective in the treatment of infections with most Candida spp.
• Single dose of 150 mg is effective in uncomplicated vaginal candidiasis.
• Oropharyngeal candidiasis: 200 mg on the first day and then 100 mg daily for at least 2 weeks.
• Thrush or esophageal candidiasis in the AIDS patient, which may be refractory to nystatin, clotrimazole, and ketoconazole.
– Dermatophytosis:
• 150 mg/w  2-6w.
• Tinea capitis: 6 mg/kg/d  2–3 weeks.
• Onychomycosis: 150 mg /w  6-9-m.
2. Systemic fungal infections:
– Especially for cryptococcal meningitis 400-800 mg q24h.
– > 800 mg q24h in unstable patient.
– Maintenance: 400 mg/day, for the initial 8 weeks in the treatment in AIDS after the patient has been
stabilized with IV amphotericin B.
– Prophylactically: for end-stage AIDS or bone marrow transplant recipients 200 mg po qd.

76. SIDE EFFECTS:
1. Gastrointestinal disturbances: Nausea, abdominal pain, diarrhea and vomiting at
doses >200 mg/day.
2. Central nervous system disturbances: Headache.
3. Liver affection: Asymptomatic liver enzyme elevation has been described, and
several cases of drug associated hepatic necrosis have been reported. Rare
deaths due to hepatic failure.
4. Allergic reactions: skin rash, morbilliform eruption, exfoliative dermatitis (rarely),
Stevens-Johnson syndrome.
5. Reversible alopecia may occur with prolonged high-dose therapy.
6. Highly teratogenic: Associated with skeletal and cardiac deformities in infants
born to women taking high doses during pregnancy and should be avoided
during pregnancy.

79. • Reversible noncompetitive inhibition of squalene epoxidase  accumulation of
intracellular squalene (fungicidal)  decrease in lanosterol production  decrease
in ergosterol  Interfere with CM synthesis.
• These agents exhibit fungicidal activity against dermatophytes and fungistatic
activity against yeasts.
• Agents:
1. Naftifine is available for topical use only in the treatment of cutaneous dermatophyte and Candida
infections.
2. Terbinafine is available for topical and systemic use in the treatment of dermatophyte skin and nail
infections.

82. • Terbinafine is a synthetic allylamine antifungal agent. It is
especially effective against dermatophytes.
• Antifungal spectra  Epidermophyton spp., Trichophyton spp.
• More selective to fungal enzyme so it appears to be a relatively
safe drug. Side effects, usually minor, arise occasionally. Serious
side effects occur rarely.

83. ADME:
• It is absorbed well when taken orally, with or without food.
• It is bound to proteins such as albumin in the circulating blood and
becomes concentrated in fat cells (lipophilic) and within skin (epidermal
& sebum), hair and nails.
• Skin concentrations may be up to 75-fold higher than those in the blood.
• It may persist in the skin for up to 8 weeks after the drug has been
discontinued and in the nails for up to a year.
• Metabolized in the liver into inactive compounds then slowly eliminated
in faeces and urine. Doses may need to be reduced in the presence of
kidney disease.

84. USES & DOSAGES:
• Only in dermatophytosis.
• The oral dose of terbinafine for adults is 250 mg daily.
1. Tinea corporis, tinea cruris, tinea pedis, tinea manuum: 1 to 4 weeks.
2. Tinea unguium: for 6 weeks (fingernails) or 12 weeks (toenails).
3. Tinea capitis for children over 2 years old, the tablets can be hidden in
food – the tablets taste unpleasant taken for 4 weeks:
– Weight <20 kg  62.5 mg/day
– Weight 20-40 kg  125 mg/day
– Weight >40 kg  250 mg/day
– Sometimes, if the fungal infection does not clear, the dose in children may
need to be increased.
• Treatment can be repeated if necessary.

85. SIDE EFFECTS:
1. Gastrointestinal disturbances: nausea, feeling of fullness, diarrhea, abdominal pain.
2. Central nervous system disturbances: Headache, dizziness, taste disturbance, loss of
appetite (uncommon, <1%), visual disturbance.
3. Liver affection: Elevated liver enzymes so tests for liver function should be performed
before and during treatment. But sever liver disease is rare (<0.01%).
4. Allergic reactions: including urticaria (common, <10%), morbilliform eruption and
Stevens-Johnson and toxic epidermal necrolysis (very rare, but potentially dangerous,
<0.01%), pustular psoriasis, subacute cutaneous lupus erythematosus.
5. Painful muscles and joints.
6. Reduced neutrophil white blood cell count (very rare, <0.01%).

86. DRUG INTERACTIONS:
• Terbinafine does not generally alter the concentration of
other medications.
1. Rifampicin results in a decrease in the concentration of
terbinafine by doubling its rate of clearance.
2. Cimetidine may increase the concentration of terbinafine.
3. Cyclosporine terbinafine increases its clearance.
4. Antidepressants: SSRIs, MAO i, TCA terbinafine may increase
their serum levels and toxic effects.

88. • Is an antimetabolite analogue of cytosine that was
originally synthesized for possible use as an
antineoplastic agent. 5-FC is converted to 5-fluorouracil
inside the cell by the fungal enzyme cytosine deaminase.
• The active metabolite 5-fluorouracil interferes with
fungal DNA synthesis by inhibiting thymidylate
synthetase. Incorporation of these metabolites into
fungal RNA inhibits protein synthesis.
• Flucytosine has a significant antifungal activity against
Candida spp. and the fungal organisms responsible for
chromomycosis.

90. • Caspofungin is a semisynthetic lipopeptide. It
inhibits the synthesis of β-glucan, a cell wall
component of filamentous fungi.
• Echinocandins are available only for IV
administration.
• Caspofungin is approved for the treatment of
invasive aspergillosis in patients not responding to
amphotericin B, and itraconazole.
• Adverse effects are mediated through histamine
release: facial flushing, rash, fever, and pruritus.

91. • Bolognia 3rd ed.
• http://dermnetnz.org
• Google images
• Dr. Mrs Borkar (Presentation)
• Mechanisms in Medicine