• 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.

• 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.

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

DRUG CLASS AGENTS

IMIDAZOLES

ClotrimazoleEconazoleKetoconazoleMiconazole

OxiconazoleSertaconazoleTerconazoleTioconazole

ButoconazoleSulconazole

ALLYLAMINES Terbinafine Naftifine

BENZYLAMINE Butenafine

THIOCARBAMATES Tolnaftate Tolciclate

POLYENES* Nystatin* Amphotericin B*

HYDROXYPYRIDONE Ciclopirox olamine

OTHERSWhitfield's ointment Selenium sulfide

Undecylenic acidIodoquinol

Clioquinol

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, tineabarbae and onychomycosis.

3. YEAST infections; mucocutaneous candidiasis, pityriasisversicolor.

4. SEBORRHEIC DERMATITIS; Ketoconazole, selenium sulfide & ciclopirox olamine.

5. MOULD skin infections such as tinea nigra.

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.

DRUG CLASS MECHANISMS OF ACTION

IMIDAZOLES

• Inhibition of fungal cytochrome P450-dependent 14-α-demethylaseprevents 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.

ALLYLAMINESBENZYLAMINE

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 inhibitsrespiration, 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.

• The creams are applied to the affected area twice daily for two to four weeks, including a margin of severalcentimetres 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 aspossible before swallowing or expectorating repeated 4 times/d.

• 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 contactdermatitis.

• Clioquinol can cause discoloration of clothes, skin, hair and nails.

I. Antifungals inhibiting synthesis of THE CELL WALL– Caspofungin

II. Antifungals altering PERMEABILITY OF THE CELL MEMBRANE1. Polyenes2. Azoles3. Allylamines

III. Antifungals disrupt MICROTUBULE FUNCTION Inhibit mitosis – Griseofulvin

IV. Antifungals inhibiting synthesis of THE NUCLEIC ACIDS– Flucytosine

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.

• Amphotericin B and Nystatin interacts with ergosterols, forms pores that increase membrane permeability and allow leakage of intracellular ions & macromolecules from fungal cell celldeath.

• 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 topicaltreatment of superficial infections caused by C. albicans.

• Antifungal agent with the broadest spectrum of activity

• Drug of choice for the vast majority of life-threateningsystemic fungal infections.

• Intrathecal infusion of amphotericin B is useful in patients with meningitis caused by Coccidioides.

• 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.

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, stoppingthe progression of dermatophyte infection.

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.

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.

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.

Griseofulvin Side Effects MnemonicDo 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

CONTRAINDICATIONS:1. Porphyrias

2. Liver failure

3. Pregnancy as there is a slight risk of malformation of the fetus.

DRUG INTERACTIONS:

1. Griseofulvin interacts with alcohol and can induce a disulfiram-likereaction 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

• 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

MOA:• Inhibition of fungal cytochrome P450-dependent 14-α-

demethylase prevents synthesis of ergosterol Reducedfungal membrane ergosterol concentrations result in damaged, leaky cell membranes.

• The toxicity of these drugs depends on their relative affinitiesfor mammalian and fungal cytochrome P450 enzymes.

• 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 steroidsynthesis leading to decreased testosterone and cortisol production.

• Agents:– Ketoconazole– Miconazole– Clotrimazole– Isoconazole – Tioconazole……….

• 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 mostserious 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.

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.

FORMULATION:

• Available in 200 mg tablets.

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.

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 cortisolwhich 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.

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

• In August 2013, the FDA announced that clinicians should nolonger prescribe ketoconazole (Nizoral) tablets as a first-linetherapy for any fungal infection, including Candida and dermatophyte infections, because of the risk for severe liverinjury, adrenal insufficiency, and adverse drug interactions.

• Ketoconazole tablets were also withdrawn from the market in the European Union in July 2013.

• 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. Itraconazole2. Fluconazole3. Voriconazole

• 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.

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.

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.

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.

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.

• 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.

ADME

• Bioavailability not altered by food or gastric acidity. Does not require an acidicenvironment, 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.

FORMULATIONS:

• Capsules for oral administration 50 or 150 mg.

• Powder for oral suspension 50 mg/5ml

• Intravenous solutions containing 2 mg/ml.

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.

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.

• 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 fungistaticactivity 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.

• 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 relativelysafe drug. Side effects, usually minor, arise occasionally. Serious side effects occur rarely.

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.

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.

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%).

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.

• Is an antimetabolite analogue of cytosine that was originally synthesized for possible use as an antineoplastic agent. 5-FC is converted to 5-fluorouracilinside the cell by the fungal enzyme cytosine deaminase.

• The active metabolite 5-fluorouracil interferes with fungal DNA synthesis by inhibiting thymidylatesynthetase. 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.

• Caspofungin is a semisynthetic lipopeptide. It inhibits the synthesis of β-glucan, a cell wall component of filamentous fungi.

• Echinocandins are available only for IVadministration.

• Caspofungin is approved for the treatment of invasive aspergillosis in patients not responding to amphotericin B, and itraconazole.

• Adverse effects are mediated through histaminerelease: facial flushing, rash, fever, and pruritus.

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