FUNGAL SKIN PHARMACOLOGY DERMATOPHYTOSIS Fungal infection in humans is common and mainly due to two groups of fungi: y dermatophytes

multicellular filaments or hyphae y yeasts - unicellular forms that replicate by budding.These are usually confined to the stratum corneum, but deep mycosesinvade other tissues Dermatophyte infections Dermatophytes are fungi that live within the epidermal keratin and do not penetrate deeper structures) Dermatophyte fungi reproduce by spore formation. They infect the stratum corneum, nail and hair, and induce inflammation by delayed hypersensitivity or by metabolic effects. There are three genera: Microsporum infect skin and hair Trichophyton infect skin, nail andhair Epidermophyton infect skin and nail. Thirty species are pathogenic in humans. Zoophilic species (transmitted to humans from animals), e.g.T. verrucosum [Fig. 1), produce more inflammation than anthropophilic (human only) species.

Microsporum M. Andonni (anthropophilic) M. Cannis (zoophilic) M. Gypseum (geophilic) Epidermophyton E. Flocusum Tricophyton T. Tonsorans (anthropohilic) T. varrucosum (zoophylic) T. Violaceum (anthropohilic) T. Mentagrophyte (zoophylic) T. Rubrum (anthropohilic) T. Schoenleinii (anthropohilic)

Fungal infections could be classified into: A- Superficial fungal infections: I- Dermatophytes: - Tinea: capitis (scalp), corporis (body), inguinum (nails) and pedis (foot). II- Candida: a) Cutaneous, Vaginal, Oropharyngeal, Gastrointestinal Candidiasis. b) Mucocutaneous candidiasis in severely immunodeficient patients and can spread to deep tissues (disseminated candidiasis). Clinical presentation Tinea (Latin: worm) denotes a fungal skin infection which is often annular.The exact features depend on the site. The various presentations include: Tinea corporis ringworms(trunk and limbs).Single or multiple plaques, with scaling and erythema especially at the edges, characterize this presentation.The lesions enlarge slowly, with central clearing, leaving a ring pattern, hence 'ringworm' .Pustules or vesicles may be seen. Tinea cruris (groin). This is more common in men and is often seen in athletes ('jock itch') who may also have tinea pedis. It spreads to the upper thigh but rarely involves the scrotum. The advancing edge may be scaly, pustular or vesicular. Tinea manuum (hand). Typically, this appears as a unilateral, diffuse powdery scaling of the palm clinical features acute: blisters at edge of red areas on hands chronic: single dry scaly patch. primary fungal infection of the hand is actually quite rare; usually associated with tinea pedis with one hand and two feet affected = 1 hand 2 feet syndrome . Tinea capitis (scalp/hair). .etiology: Trichophyton tonsurans and Microsporum species epidemiology: affects children (mainly black), immunocompromised adults. very contagious and may be transmitted from barber, hats, theatre seats, pets signs and symptoms: round, scaly patches of alopecia, may see broken off hairs, if tissue reaction is acute, a Kerion (boggy, elevated, purulent inflamed nodule/plaque)may form - this may be secondarily infected by bacteria and result in scarring Tinea unguium (nails). clinical features: crumbling, distally dystrophic nails; yellowish, opaque with subungual herperkeratotic debris toenail infections usually precede fingernail infections

 Tinea pedis (athlete's foot). Athlete's foot is common in adults (especially young men), rare in children and predisposed to by communal washing, swimming baths occlusive footwear and hot weather.Itchy interdigital maceration, usually of the 4th/5th toeweb space, is most frequent. Recurrent vesiclesalso occur, . The commonest organisms are T. rubrum,T. mentagrophytes var. interdigitale and Epidermophyton floccosum. epidemiology chronic infections are common in atopics heat, humidity, occlusive footwear are predisposing factors signs and symptoms aute infection - red/white scales, vesicles, bullae, often with maceration may present as flare-up of chronic tinea pedis frequently become secondarily infected by bacteria chronic: non-pruritic, pink, scaling keratosis on soles, and sides of foot, often in a moccasin distribution sites: interdigital, especially in 4th webspace

PATHOPHYSIOLOGY OF TINEA INFXT Digestion of keratin by dermatophytes results in scaly skin, broken hairs, crumbling nails INVESTIGATION skin scrapings, hair, and nail clippings analyzed with potassium hydroxide (KOH) prep (since these fungi live as molds, look for hyphae, and mycelia) Pityriasis (tinea) versicolor Pityriasis versicolor is a chronic, often asymptomatic, fungal infection characterized by pigmentary changes and involving the trunk. Clinical presentation The condition is caused by overgrowth of the mycelial form of the commensal yeast Pityrosporum orbiculare and is particularly common in humid or tropical

conditions. In Europe it mainly affects young adults, appearing on the trunk and proximal parts of the limbs . In untanned, white Caucasians, brown or pinkish oval or round superficially scaly patches are seen, but in tanned or racially pigmented skin, hypopigmentation is found due to the release by the organism of carboxylic acids which inhibit melanogenesis. chronic asymptomatic superficial fungal infection with brown/white scaling macules epidemiology P. ovale also associated with folliculitis and seborrheic dermititis young adults, M=F predisposing factors: summer, tropical climates, Cushings syndrome, prolonged corticosteroid use signs and symptoms affected skin appears darker than surrounding skin in winter, lighter in summer (doesnt tan) sites: upper trunk most common seen on the face in dark skinned individuals pathophysiology Malassezia furfur (Pityrosporum orbiculare) that produces cicarboxylic acid > inflammatory reaction and inhibited melanin production, yielding variable pigmentation

MANAGEMENT y scrub off scales with soap and water if there any.
I- Drugs for systemic fungal infections: y 1. Amphotericin-B. y 2. Flucytosine. y 3. Azoles: - Ketoconazole, Fluconazole, Itraconazole. II- Drugs for superficial infections: y A- Drugs given systematically: y 1. Griseofulvin.(Dermatophytes) y 2. Terbenafine. (Dermatophytes). y 3. Azoles: Ketoconazole, Fluconazole, Itraconazole (Dermatophytes & Candida). y B- Drugs given topically: y 1. Nystatin (Candida). y 2. Gentian violet (Candida). y 3. Whitefield ointment (Dermatophytes). y 4. Azoles: -Ketoconazole, (Miconazole, Clotrimazole are too toxic for systemic use).

5. Terbenafine.

Superficial fungal infections are treated first with topical agents. y Systemic therapy is used in: y 1- Resistance to topical therapy, wide or inaccessible area. y 2- Severe infection of the hair, skin and the nails. Decrease immunity of patient topicals may be used as first line agents for tinea corporis/cruris and tinea pedis (interdigital type), e.g. clotrimazole or terbinafine cream applied bid, continued till one week after complete resolution of lesions. oral therapy is indicated for onychomycosis, tinea capitus, e.g. terbinafine or itraconazole itraconazole is a P-450 inhibitor. It alters metabolism of non-sedating antihistamines, cisapride,digoxin, and HMG CoA reductase inhibitors TOPICAL THERAPY Whitfield's ointment (containing benzoic acid) and imidazoles. Tinea corporis, tinea pedis and tinea cruris respond to topical creams, sprays or powders. Terbinafine cream once daily is ofteneffective. Amorolfine nail lacquer, applied once weekly, producesa 40-50% cure for tinea unguium of one or two nails. Before antifungalagents, scalp ringworm sometimes required X-irradiation.

SYSTEMIC THERAPY Tinea capitis, tinea manuum, tinea unguium and extensive tinea corporis often require systemic treatment. Tinea corporis and tinea manuum respond to griseofulvin 500 mg once a day (for an adult) for 1-2 months. Scalp ringworm requires 3 months treatment, fingernail involvement 4-8 months and toenail infection 18 months. In the elderly, fungal toenail infection often does not require any therapy. However, griseofulvin is effective in only 30% of toenail infections and 70% of fingernail infections. Griseofulvin may cause headache, nausea, gastrointestinal upset and photosensitivity, and can interact with warfarin, oral contraceptives and phenobarbital. The new anti-fungal agents, with greater efficacy and fewer side-effects, are usually preferred to griseofulvin, except in children. Terbinafine 250 mg daily, and itraconazole 100 mg daily, may be used for tinea corporis, cruris, manuum and

pedis, given for 2-4 weeks. Tinea unguium responds to terbinafine (250 mg daily) or itraconazole (200 mg daily) for 6-12 weeks Ketoconazole , though effective, is limited in use by hepatotoxicity.

YEAST INFECTIONS yeasts - unicellular forms that replicate by budding.These are usually confined to the stratum corneum, but deep mycosesinvade other tissues Candida albicans infection Candida:  Candida albicans  Candida Kruzi  Candida Tropicalis  Candida Pseudotropicalis  Candida Gullarmondi Candida albicans is a ubiquitous commensal of the mouth and gastrointestinal tract which can produce opportunistic infection. Predisposing factors include:moist and opposing skin folds, obesity or diabetes mellitus, immunosuppression, pregnancy, poor hygiene, humid environment ,wetwork occupation, use of broad-spectrum antibiotic. In a study of 1009 women in New Zealand, Candida albicans was isolated from the vaginas of 19% of apparently healthy women. Carriers experienced few or no symptoms. However, external use of irritants (such as some detergents or douches) or internal disturbances (hormonal or physiological) can perturb the normal flora, constituting lactic acid bacteria, such as lactobacilli, and an overgrowth of yeast can result in noticeable symptoms. Pregnancy, the use of oral contraceptives, engaging in vaginal sex immediately and without cleansing after anal sex, and using lubricants containing glycerin have been found to be causally related to yeast infections. Diabetes mellitus and the use of antibiotics are also linked to an increased incidence of yeast infections. Candidiasis can be sexually transmitted from men to women, but only rarely from a woman to a man. Diet has been found to be the cause in some animals. Hormone Replacement Therapy and infertility treatments may also be predisposing factors.

Clinical presentation In infection, hyphal forms of C. albicans are seen in the stratum corneum. Infection may present as: Genital. Thrush commonly appears as an itchy, sore vulvovaginitis.White plaques adhere to inflamed mucous membranes and a white vaginal discharge may occur. Males develop similar changes on the penis. It can be spread by sexual intercourse. Intertrigo. Super-infection with C. albicans, and often also with bacteria, gives a moist, glazed and macerated appearance to the submammary, axillary or inguinal body folds. The interdigital clefts are involved in wetworkers who do not dry their hands properly. Mucocutaneous candidiasis. This rare, sometimes inherited disorder of immune deficiency starts in infancy.Chronic C. albicans intertrigo with nail and mouth infections is seen. Oral. White plaques adhere to an erythematous buccal mucosa.Broad-spectrum antibiotics, false teeth and poor oral hygiene predispose. Angular stomatitis may co-exist. Systemic. Systemic candidiasis can occur in immunosuppressed patients. Red nodules are seen in the skin. Management Candida albicans infections must be differentiated from other conditions. General measures are important. Body folds are separated and kept dry with dusting powder.Hands are dried carefully and oral hygiene improved. Systemic antibiotics may need to be stopped .Specific agents against Candida are used topically and systemically. Topical therapy Magenta paint is useful for body folds,but is messy because of its colour. Imidazoles are effective and available topical,as creams, powders and lotions. For oral Candida, use amphotericin,nystatin or miconazole as lozenges,suspension or gels.

Systemic therapy Bowel carriage may be reduced in recurrent candidiasis by oral nystatin. Itraconazole 100 mg daily, or fluconazole 50 mg daily, but not griseofulvin, can

be given as a short course for persistent C. albicans infections and in the long term for mucocutaneous candidiasis. Vaginal candidiasis is treated by a single dose of 500 mg clotrimazole or 150mg fluconazole 150 mg econazole or nystatin pessaries as a pessary, or with itraconazole or by mouth TREATMENT OF FUNGAL INFECTION An antifungal medication is a medication used to treat fungal infections such as athlete's foot, ringworm, candidiasis (thrush), serious systemic infections such as cryptococcal meningitis, and others. MECHANISM OF ACTIONS OF ANTIFUNGAL Antifungals work by exploiting differences between mammalian and fungal cells to kill the fungal organism without dangerous effects on the host. Unlike bacteria, both fungi and humans are eukaryotes. Thus fungal and human cells are similar at the molecular level. This makes it more difficult to find or design drugs that target fungi without affecting human cells. As a consequence, many antifungal drugs cause side-effects. Some of these side-effects can be life-threatening if the drugs are not used properly. Apart from side-effects like liver-damage or affecting estrogen levels, many antifungal medicines can cause allergic reactions in people. For example, the azole group of drugs is known to have caused anaphylaxis. There are also many drug interactions. Patients must read in detail the enclosed data sheet(s) of the medicine. For example, the azole antifungals such as ketoconazole or itraconazole can be both substrates and inhibitors of the Pglycoprotein, which (among other functions) excretes toxins and drugs into the intestines. Azole antifungals also are both substrates and inhibitors of the cytochrome P450 family CYP3A4, causing increased concentration when administering, for example, calcium channel blockers, immunosuppressants, chemotherapeutic drugs, benzodiazepines, tricyclic antidepressants, macrolides and SSRIs. Classes Polyene antifungals: Polyene antimycotic

A polyene is a molecule with multiple conjugated double bonds. A polyene antifungal is a macrocyclic polyene with a heavily hydroxylated region on the ring opposite the conjugated system. This makes polyene antifungals amphiphilic. The polyene antimycotics bind with sterols in the fungal cell membrane, principally ergosterol. This changes the transition temperature (Tg) of the cell membrane, thereby placing the membrane in a less fluid, more crystalline state. As a result, the cell's contents including monovalent ions (K+, Na+, H+, and Cl-), small organic molecules leak and this is regarded one of the primary ways cell dies.Animal cells contain cholesterol instead of ergosterol and so they are much less susceptible. However, at therapeutic doses, some amphotericin B may bind to animal membrane cholesterol, increasing the risk of human toxicity. Amphotericin B is nephrotoxic when given intravenously. As a polyene's hydrophobic chain is shortened, its sterol binding activity is increased. Therefore, further reduction of the hydrophobic chain may result in it binding to cholesterol, making it toxic to animals.
y y y

Natamycin - 33 Carbons, binds well to ergosterol Amphotericin B Candicin

Imidazole, triazole, and thiazole antifungals  Azole antifungal drugs inhibit the enzyme lanosterol 14 -demethylase; the enzyme necessary to convert lanosterol to ergosterol. Depletion of ergosterol in fungal membrane disrupts the structure and many functions of fungal membrane leading to inhibition of fungal growth. Damages fungal cell wall membrane by inhibiting biosynthesis of ergosterol. Membrane permeability is increased, causing nutrients to leak out and resulting in fungal cell death.  Adult Dose- Apply to affected area qid.

Imidazoles
y y y y y y y

Miconazole Ketoconazole Clotrimazole Econazole Omoconazole Bifonazole Butoconazole

y y y y y y

Fenticonazole Isoconazole Oxiconazole Sertaconazole Sulconazole Tioconazole

Triazoles
y y y y y y y y

Fluconazole Itraconazole Isavuconazole Ravuconazole Posaconazole Voriconazole Terconazole Albaconazole

Thiazoles
y

Abafungin

Allylamines Allylamines inhibit squalene epoxidase, another enzyme required for ergosterol synthesis: y Terbinafine y Naftifine y Butenafine Echinocandins Echinocandins may be used for systemic fungal infections in immunocompromised patients, they inhibit the synthesis of glucan in the cell wall via the enzyme 1,3glucan synthase:
y y y

Anidulafungin Caspofungin Micafungin

Echinocandins are poorly absorbed when administered orally. When administered by injection they will reach most tissues and organs with concentrations sufficient to treat localized and systemic fungal infections. Others  A low-to-medium potency topical corticosteroid can be added to the topical antifungal regimen to relieve symptoms. The steroid can provide rapid relief from the inflammatory component of the infection, but the steroid should only be applied for the first few days of treatment. Prolonged use of steroids can lead to persistent and recurrent infections, longer duration of treatment regimens, and adverse effects of skin atrophy, striae, and telangiectasias.

y y y

y y y y y y

Polygodial- strong and fast-acting in-vitro antifungal activity against Candida albicans. Benzoic acid - has antifugal properties but must be combined with a keratolytic agent such as in Whitfield's Ointment Ciclopirox - (ciclopirox olamine), most useful against Tinea versicolour a topical fungicidal agent.MOA- Interferes with synthesis of DNA, RNA, and protein by inhibiting the transport of essential elements in fungal cells.DoseMassage into affected areas bid; re-evaluate the diagnosis if no improvem Tolnaftate Undecylenic acid - an unsaturated fatty acid derived from natural castor oil; fungistatic as well as anti-bacterial and anti-viral Flucytosine or 5-fluorocytosine - an antimetabolite Griseofulvin - binds to polymerized microtubules and inhibits fungal mitosis Haloprogin - discontinued due to the emergence of more modern antifungals with fewer side effects Sodium bicarbonate (NaHCO3) - shown effective against green mold on citrus under refrigeration and powdery mildew on rose plants y Allicin - created from crushing garlic y Tea tree oil - ISO 4730 ("Oil of Melaleuca, Terpinen-4-ol type") y Citronella oil - obtained from the leaves and stems of different species of Cymbopogon (Lemon grass) y Iodine - Lugol's iodine y olive leaf y orange oil

y y y y y y y y

palmarosa oil patchouli lemon myrtle Neem Seed Oil Coconut Oil - medium chain triglycerides in the oil have antifungal activities Zinc - in dietary supplements or natural food sources, including pumpkin seeds and chick peas Selenium - in dietary supplements or natural food sources, particularly Brazil nuts Horopito (Pseudowintera colorata) leaf - contains the anti-fungal compound polygodial