1. 5. Antifungal Agents Pharmacognosy IV PHG 423 Dr/ Abdulaziz Saeedan Pharmacy College 1

2. Fungal infections (Mycotic infections – Mycosis) eukaryotic microorganisms  Fungi are a group of eukaryotic microorganisms which involves molds and yeasts.  Fungi grow best in a warm, moist environment such as shoes, socks, swimming pools and the floors of public showers. NOTE: ergosterol  A sterol called ergosterol is a common constituent in fungal cell membrane but absent in human cell membrane. Consequently, ergosterol may represent a safe target for some antifungal drugs.  Types of fungal infections: 1- Superficial infections :  Affect skin, hair, nails, mucous membranes and vagina. Ex: Ringworm (Tinea) and Candidiasis. 2- Deep (Systemic) infections:  Affect internal organs. Ex: Aspergillosis, Cryptococcosis, Histoplasmosis, Candidiasis.

3. Superficial infections A- Ringworm (Tinea)  There are different types of ringworm: 1- Tinea Versicolor: It is the ringworm that affects skin of the neck, upper back, shoulders, and chest producing small white-to-pink-to- dark-brown spots on the skin.  It caused by a fungus (yeast) known as Malassezia. 2- Tinea corporis: round red spots  It is the ringworm that affects skin producing the characteristic round red spots.  It caused by mold-like fungi called dermatophytes (Trichophyton – Microsporum).

4. 3- Tinea barbae: It is the ringworm that affects skin of the face and neck that is covered with hair. inflammation, crusting and itching  It is characterized by inflammation, crusting and itching. It can also cause hair loss in the affected area.  It caused by dermatophytes. 4- Tinea capitis: It is the ringworm that affects the scalp.  It is characterized by scaling and bald spots.  It caused by dermatophytes 5- Tinea pedis (Athlete’s foot):  It is the ringworm that affects the feet especially the region between the toes, causing scaling and inflammation.  It caused by dermatophytes

5. 6- Tinea unguium (Onychomycosis): It is the ringworm that affects the nails making them thick and yellowish in colour.  It caused by dermatophytes B- Candidiasis  There are different types of candidiasis: 1- Cutaneous candidiasis  Cutaneous candidiasis is an infection of the skin with Candida albicans (yeast-like fungi) 2- Oral candidiasis (Oral thrush)  Oral candidiasis is an infection of the oral cavity and tongue with Candida albicans. 3- Vaginal candidiasis (Vaginal thrush)  Vaginal candidiasis is an infection of the vagina with Candida albicans.

6. NOTE:  Candida albicans is often present in small populations in the mouth, digestive tract, vagina and on the skin.  Usually, Candida does not cause symptoms but in immunocompromised individuals it may cause life-threatening illness.

7. Systemic infections  Systemic fungal infections can be serious and sometimes, life-threatening. 1.Aspergillosis: is a fungal disease affecting any area of the body, but most commonly affects the lungs.  The common symptoms are weight loss, chronic cough and fatigue. 2. Cryptococcosis: is a fungal disease affecting meninges causing Cryptococcal meningitis.  The common symptoms are weight loss, fatigue, blurred vision and stiff neck. 3. Histoplasmosis is a fungal disease causing serious infections of the lung and other organs.  The common symptoms are fever, cough and chest pains. 4. Systemic Candidiasis may include the brain, heart, kidneys, liver and it can be life- threatening.

8. Antifungal agents  Antifungal agents are drugs that destroys or prevents the growth of fungal pathogens.  The choice of antifungal drug, its dose and the duration of treatment depends on: 1- Type of the fungus. 2- The site of infection.  Types of antifungal drugs: 1- Topical antifungal drugs:  These are drugs that applied to skin and oral cavity in case of superficial fungal infections. 2- Systemic antifungal drugs:  These are drugs that taken by mouth or by injection in case of systemic fungal infections.

9. 1- Polyene antibiotics. Ex: Amphotericin B and Nystatin  Polyene means many double bonds.  Polyene antibiotics are products of Streptomyces species.  MOA:  Polyene antibiotics interact with ergosterols of the fungal membranes forming channels through which intracellular ions (Na, K) and other small molecules leak from the inside of the fungal cell to the outside leading to fungal death.

10. Amphotercin B:  It is one of the polyene antibiotics which act as topical and systemic antimycotic.  Administration:  Oral: Not absorbed from GI tract, So oral administration treats only fungal infection of the GI tract.  Topical: Used topically for superficial fungal infections.  IV: For systemic fungal infections.  Spectrum of Activity:  Amphotericin B has a broad spectrum activity.  It acts against most species of fungi especially Candida, Aspergillus, Histoplasma and Cryptococcus species.  MOA ……… ergosterol ……………

11.  Adverse effects 1- Immediate adverse effects:  Oral administration causes GI irritation; vomiting.  Topical administration causes local irritation.  IV administration may induces some serious side effects in the form of fever, anaphylaxis and hypotension. o These side effects can be avoided by : a. Slowing injection rate. b. Premedication with antipyretics, antihistaminics or corticosteroids. 2- Delayed adverse effects:  The most common delayed adverse effect following IV injection of amphotericin B is nephrotoxicity.  Uses:  Amphotericin B is the main antifungal drug that used for treatment of life-threatening fungal infections including Candidiasis, Aspergillosis, Histoplasmosis, Cryptococcosis (Cryptococcal meningitis).

12. Nystatin  It is one of the polyene antibiotics which act as topical antimycotic.  Administration:  Oral: Not absorbed from GI tract, So oral administration treats only fungal infection of the GI tract.  Topical: Used topically for superficial fungal infections.  Injections: Nystatin is too toxic – Not used by injection.  Spectrum of Activity:  It has a broad-spectrum activity. !!!! NOTE:  The advantage of the broad-spectrum activity of nystatin is antagonized by host toxicity. Therefore, it is limited to oral and topical use against Candida species.

13.  MOA ……… ergosterol ……………  Adverse effects: Mild when used topically and orally  Uses: 1- Oral candidiasis (thrush). 2- Intestinal candidiasis. 3- Vaginal candidiasis. 4- Cutaneous candidiasis. NOTES:  Nystatin is known to be ineffective against dermatophytes. azole  Candidal infections that do not respond well to topical therapy of nystatin will require a systemically active azole such as fluconazole.

14. 2- Azole Antifungal Drugs:  Azoles are a group of synthetic antifungal agents.  They have antifungal, antibacterial, antiprotozoal and anthelminthic activities  They are classified into 2 groups : A- Imidazole group : A- Imidazole group : Ketoconazole. B- Triazole group: B- Triazole group: Itraconazole, Fluconazole.  MOA:  Azoles inhibit the fungal cytochrome P-450 enzyme which are responsible for synthesis of ergosterol, (the major sterol of fungal cell membrane) so interfere with the synthesis of fungal membranes.

15. A- Imidazole group: Ketoconazole  It is one of imidazole group which act as topical and systemic antimycotic.  Administration:  Oral: Ketoconazole is well absorbed from GI tract.  Topical: Used topically for superficial fungal infections.  Injections: Ketoconazole is soluble only at pH of less than 3 and is therefore not available in injectable form.  Spectrum of Activity:  Ketoconazole is active against Dermatophytes and Candida.  MOA ………… cytochrome P-450 enzyme ……………………..

16.  Adverse Effects:  The most common adverse effects of oral ketoconazole involve nausea and vomiting.  Symptoms may be minimized by taking the drug with food.  Ketoconazole inhibits the synthesis of gonadal steroids (testosterone) leading to impotence and decreased libido in men.  It inhibits human P-450 hepatic enzymes.  Uses: 1- Used topically for:  Ringworm.  Oral, cutaneous and vaginal candidiasis. 2- Used orally for systemic candidiasis.

17. B- Triazole group (Itraconazole – Fluconazole): i. Itraconazole: It is one of triazole group which act as systemic antimycotic.  Administration:  Oral: It is well absorbed from GI tract. Itraconazole is only available in oral form.  Spectrum of Activity:  It has a broad spectrum activity. It is effective against Dermatophytes, Candida, and Aspergillus.  MOA ………… cytochrome P-450 enzyme ……………………..  Adverse Effects:  The most common side effects of itraconazole include nausea, vomiting and diarrhea.  Unlike ketoconazole, itraconazole has a minimal inhibitory effect on the synthesis of gonadal steroids (testosterone).  Uses:  Ringworm.  All forms of Candidiasis.  Aspergillosis

18. ii. Fluconazole:  It is one of Triazole group which act as systemic antimycotic.  Administration:  Oral: It is well absorbed from GI tract.  IV  Spectrum of Activity:  It has a broad spectrum activity like Itraconazole. It is effective against Dermatophytes, Candida, and Aspergillus in addition to Cryptococcus and Histoplasma.  The main advantage of fluconazole is penetration into the CSF to provide coverage of meningeal infections.  MOA ………… cytochrome P-450 enzyme ……………………..

19.  Adverse Effects:  The most common side effects of fluconazole are nausea, vomiting, diarrhea, abdominal pain, headache and skin rashes.  In contrast to ketoconazole, fluconazole does not interfere with synthesis of gonadal steroids (testosterone).  Uses:  Ringworm.  All forms of Candidiasis.  Aspergillosis  Cryptococcal meningitis  Histoplasmosis. NOTE: ONLY AZOLE  Fluconazole is the ONLY AZOLE that penetrates the CNS so used for treatment of cryptococcal meningitis.

20. 3- Antimetabolite Antifungal Drugs Ex: Flucytosine (5-Fluorocytosine)  It is a cytotoxic drug.  It is one of the antimetabolite antifungals which act as systemic antimycotic.  It is rarely used as a single agent due to the rapid development of resistance  Usually given in combination with amphotericin B.  Administration:  Oral: It is well absorbed from GI tract. - Flucytosine is only administered orally.  Spectrum of Activity:  Flucytosine has a narrow spectrum of activity against Candida and Cryptococcus.  MOA:  Susceptible fungi contain cytosine deaminase enzymes (Not in human cell) which converts flucytosine to 5-fluorouracil.  5-fluorouracil inhibits thymidylate synthetase enzyme SO inhibits the synthesis of fungal DNA.

21. When used in combination with amphotericin B:  Amphotericin B increases the permeability of fungal membrane SO flucytosine can penetrate the membrane of resistant fungi.  Adverse effects:  The main serious adverse effect is bone marrow suppression (anemia, leukopenia, thrombocytopenia). The suppression is usually reversible.  Alopecia.  Nausea, vomiting, diarrhea  Because of possible teratogenicity, flucytosine is contraindicated in pregnancy.  Uses:  It used orally with amphotericin B for treatment of : 1- Severe Candidiasis. 2- Cryptococcal meningitis.

22. 4- Other Antifungal Agents  Griseofulvin is an antifungal antibiotic produced by Penicillium griseofulvum.  Administration:  Oral: It is well absorbed from GI tract.  It is absorbed after oral administration then concentrated in the keratin layer of skin, hair and nails.  Spectrum of Activity:  Griseofulvin has a narrow spectrum of activity. It is active against dermatophytes.  MOA:  It penetrates the fungal cell and disrupts the mitotic spindle, so inhibit the fungal mitosis.  Adverse effects ;  Griseofulvin requires a long treatment time (12 to 18 months).  GIT disturbance, Peripheral neuritis, mental confusion, fatigue, blurred vision in addition to induction of cytochrome P-450 enzymes  Uses:  Griseofulvin is the drug of choice for treatment of ringworm.  Ineffective topically.