ANTI-FUNGAL DRUG AGENTS

1. Pharmacology ANTI-FUNGAL DRUG AGENTS

2. Fungal Infections • Fungi are a very large and diverse group of microorganisms that compromise both yeast and molds. • Yeast are single-celled fungi that reproduce by budding and are actually very useful organisms. They are used in baking and alcoholic beverages. • Molds are multicellular and are characterized by long, branching filaments called hyphae, which entwine to form a (mat) called a mycelium. Some fungi are part of the normal flora of the skin, mouth, intestines, and vagina.

3. Continue • The infection caused by a fungus can also be called a mycosis, but there are very few fungi that cause such infections. Those that do are termed pathologic fungi, and the infections they cause range in severity from being mild and superficial to severe and life-threatening.

4. Continue • These infections can be contracted by several different routes: • Ingested orally • Implanted under the skin after injury • They can be inhaled • There are four major general types of mycotic infections: • Systemic • Cutaneous • Subcutaneous • Superficial

5. Continue • The most severe systemic fungal infections generally afflict persons whose host defenses are compromised. Commonly these are patients who have received organ transplants and are on immunosuppressive drug therapy, cancer patients and AIDS patients. These may result in an over growth of candida albicans, followed by the development of a systemic infection.

6. Introduction • The drugs used to treat fungal infections are called antifungal agents. Systemic mycotic infections and some cutaneous or subcutaneous mycoses are treated with oral or parenterally agents. • One difficulty that has slowed the development of new agents is that frequently the chemical concentrations required for these experimental agents to be effective cannot be tolerated by human beings.

7. Continue • Following is a list of those agents that have met with success in the treatment of systemic and severe cutaneous or subcutaneous mycoses: • Amphotericin B • Fluconazole • Flucytocine • Griseofulvin • Itraconazole • Miconazole • Nystatin

8. Continue • Topical antifungal are most commonly used in the treatment of oral and vaginal candisasis. Following is a list of those topical antifungals approved for clinical use: • Amphotericin B • Butoconazole • Ciclopirox • Clotrimazole • Miconazole • Nystatin • Terbinavine • Sodium thiosulfate • Ketoconazole

9. Classification of Drugs • The antifungals agents can be broken down in to four major groups based on their chemical structures: • Polyenes, e.g Amphotericin B and Nystatin • Flucytosine • Azoles, e.g Ketoconazole and Miconazole • Griseofulvin

10. Mechanism of action • The mechanisms of action of the various antifungal agents differ depending on which of the four groups of agents they belong to. • The polyenes act by binding sterols in the cell membranes of fungi, the main sterol in the fungi is ergosterol. The question is human being has sterol then how do we prevent damage in the human cell?

11. Continue • The answer of this question polyene antifungal do not bind to human cell membranes, and therefore do not kill human cells, because polyene has stronger affinity for ergosterol than for cholesterol. Once the polyene binds to the ergosterol, a channel forms in the fungal cell membrane that allows potassium and magnesium ions to leak out of the cell. This loss of ions causes fungal cellular metabolism to be altered, and hence death of the cell.

12. Continue • Flucytosine, also known as 5-fluorocytosine. Once the 5-fluorouracil is inside the fungal cell, it interferes with DNA synthesis by incorporating itself in to the fungal pathway that produces DNA, with the result that the DNA needed for the fungal cell metabolism is lacking and the cell dies.

13. Continue • Azoles act as either fungistatic or fungicidal agents, depending on their concentration in the fungus. Inhibit production of ergosterol and this allows potassium to escape from the fungi cell membrane and lastly fungi cell dies. • Griseofulvin works by preventing mitosis or reproduction of fungi by binding to microtubules. It has also been proposed that Griseofulvin causes the production of defective DNA, which is then unable to replicate.

14. Therapeutic uses • used candiasis (oral, vaginal e.t.c) • used in Aspergillosis • used in histoplasmosis • used in fungal septicemia • used in Coccidiodomycosis • used in cryptococcal meningitis

15. Aspergillosis • Infection caused by the aspergillus fungus or one of it is mold species. • Invasive aspergillosis is an opportunistic infection that affects people with immunodeficiencies. the primary infection is usually pneumonia, but the brain, kidney, and heart valves may also be affected. • It is treated with I.V amphotericin B or long term oral itracanazole.

16. Histolasmosis • A systemic fungal respiratory disease caused by histoplasma capsulatum. The reservoir for this fungus is in soil with a high organis content, old chicken houses. • It is a common opportunistic infection. Signs are fever, anemia, enlarged spleen, leukopenia, adrenal necrosis and pneumonia. • The treatment is amphotericin B or ketoconazole.

17. Coccidiodomycosis • Infection with the pathogenic fungus coccidio-immitis. Found in the soil. It is seen in earthquakes, during construction. Persons who inhale the spores may develop active or subclinical infection. • Treatment: most patients with primary infection recover with out therapy. Amphotericin B is recommended 1-3 months.

18. Blastomycosis • Infection caused by inhalation of the conidia of blastomyces dermatitidis. This rare fungal infection may produce inflammatory lesions of the skin (cutaneous), lungs or generalized invasion of skin, bones, CNS, and the kidney. • Treatment is amphotericin B and Ketoconazole.

19. Dermatophytosis • It is causes by a fungal parasite that grows the skin of the body, and it is known as dermatophyte fungal infection. • They cause skin diseases like eczema, tinea, ringworm. • The treatment is Griseofulvin or the azoles and terbinafine.

20. Chromomycosis • A chronic fungal skin infection marked by itching and warty plaques on the skin and subcutaneous swelling of the feet and the legs and other exposed areas. • Various fungus have been implicated including phialophora verrucosa. • The treatment includes amphotericin B and Flucytosine.

21. Side-effects • Headache • Renal toxicity • Potassium loss • Nausea • Vomiting • Photosensitivity • Anaphylaxis • Rash • Tachycardia • Anorexia • Flushing • Impotence

22. Amphotericin B • It is obtained from streptomyces nodosus. • The polyenes possess a macrocyclic ring, one side of which has several conjugated double bonds and is highly lipophilic, while the other side is hydrophilic with many OH groups. • Amphotericin B is active against a wide range of yeasts and fungi candida albicans, histoplasmacapsulatum, cryptococcusneoformans, blastomyces dermatitides, and coccidiodesimmitis.

23. Continue • Amphotericin isn't orally absorbed. • It can be given orally for intestinal candisasis without systemic toxicity. • Administered I.V as a suspension made with the help of deoxycholate. • It gets widely distributed in the body, but the penetration in CSF is poor.

24. Continue • It is metabolized in the liver. • It has half life of 15 days. • Excretion occurs slowly both in urine and bile, but urinary concentration of active drug is low. • Orally can be administered 50-100mg QID. • For i.v 0.3mg/kg or 0.7mg/kg. • The total dose of amphotericin for majority of cases is 3-4g given over 2-3 months. • Intrathecal injection of 0.5mg twice weekly has been given in fungal meningitis.

25. Uses • Amphotericin B can be applied topically for oral, vaginal and cutaneous candisasis and otomycosis. • It is the most effective drug for various types of systemic mycosis and is the gold standard of antifungal therapy. However, because of higher toxicity of amphotericin B, the azole antifungals are now preferred in conditions where their efficacy approaches.

26. Drug interactions • Flucytosine has supra-additive action with amphotericin B in the case of fungi sensitive to fungus. • Rifampin and Minocycline , though not antifungal in their own right but potentiate amphotericin action.

27. Adverse effects • Chills • Fever • Nausea • Vomiting • Dyspnea • Hypokalemia • Nephrotoxicity

28. AMPHOTERICIN B TOXICITY • ID/CC: During ward rounds, a 28 year old HIV positive female patient complains that after a period of improvement since her administration 3 days ago, she now feels very sick, with high fever, marked lightheadedness, headache, and myalgias. • HPI: She was admitted because of cryptococcal meningitis and was started on amphotericin B.

29. Continue • PE: VS: tachycardia (HR 93); hypotension (BP 90/55); fever (39.3 centigrade); tachypnea. PE: nuchal rigidity resolved, mental status improved. • Labs: CBC: mild anemia; normal leukocytes. Lytes: hypokalemia. BUN and creatinine moderately elevated.

30. Continue • Treatment: If the reaction is severe, it may be necessary to lower the dosage of amphotericin B, use a liposomal form, or change to Fluconazole. Antipyretics, antihistamines, and corticosteroids may lessen febrile symptoms; heparin can decrease the risk of thrombophebitis. • Discussion: The mechanism of action of amphotericin B is by binding to ergosterol in fungi and forming membrane pores. Toxicities include arrhythmias, chills and fever, hypotension and nepthrotoxicity.

31. Nystatin • It is obtained streptomyces nourseia. • Nystatin has similar structure with amphotericin B and has the same pore-forming mechanism of action. It is too toxic for systemic use and is only used topically. It is not absorbed from skin, mucous membranes, or the gastrointestinal tract.

32. Continue • Nystatin is active against most Candida species and is most commonly used for suppression of local candidal infections. Nystatin is used in the treatment of oropharyngeal thrush, vaginal candidiasis. • It is available 1 lac U ,5 lac U vaginal tab, 1 lac U per g for eye ointment. (1mg = 2000 U). • It is available orally as suspension, topically 2% cream.

33. Griseofulvin • Griseofulvin is a fungistatic and used is in the treatment of dermatophytosis. Absorption is improved when it is given with fatty foods. Griseofulvin is deposited in newly forming skin where it binds to keratin, protecting the skin from new infection.

34. Continue • It must be administered for 2-6 weeks for skin and hair infections to allow the replacement of infected keratin by the resistant structures. Nail infections may require therapy for months to allow regrowth of the new protected nail and is often followed by relapse.

35. Continue • It is dose is 125mg- 250mg QID with meals, duration depends the location. • Body skin: 3 weeks, palms and soles: 4 to 6 weeks, finger nails: 4 to 6 months, toe nails: 8 to 12 months.

36. Adverse effects and drug interactions • Adverse effects include an allergic syndrome much like serum sickness, hepatitis, and drug interactions with warfarin and phenobarbital, oral contraceptives and alcohols. • Griseofulvin has been largely replaced by newer antifungal medications such as itraconazole and terbinafine.

37. Flucytosine • Flucytosine is related to fluorouracil (5-FU). Its spectrum of action is much narrower than that of amphotericin B. It is well absorbed orally. It is poorly protein-bound and penetrates well into all body fluid compartments including the CSF. It is eliminated by glomerular filtration. Toxicity is more likely to occur in AIDS patients and in the presence of renal insufficiency.

38. Continue • Flucytosine is converted intracellularly first to 5-FU and then to 5-fluorodeoxyuridine monophosphate (F-dUMP) and fluorouridine triphosphate (FUTP), which inhibit DNA and RNA synthesis, respectively.

39. Clinical use • Active against Cryptococcus neoformans, some Candida species, and thedematiaceous molds that cause chromoblastomycosis. Clinical use at present is confined to combination therapy, either with amphotericin B for cryptococcal meningitis or with itraconazole for chromoblastomycosis.

40. Adverse Effects • The adverse effects of flucytosine result from metabolism (intestinal flora) tothe toxic antineoplastic compound flucytosine. Bone marrow toxicity with anemia, leukopenia, and thrombocytopenia are the most common adverse effects, with derangement of liver enzymes occurring less frequently.

41. Azoles • Azoles are synthetic compounds that can be classified as Imidazoles and Triazoles. The Imidazoles consist of Ketoconazole, Miconazole, and Clotrimazole. • The triazoles include Itraconazole and Fluconazole.

42. Continue • Azoles are active against many Candida species, Cryptococcus neoformans, the endemic mycoses (blastomycosis, coccidioidomycosis), the dermatophytes, and, Aspergillus infections (itraconazole). Adverse Effects: The azoles are relatively nontoxic.

43. Adverse effects • The most common adverse reaction is minor gastrointestinal upset, Most azoles cause abnormalities in liver enzymes and, very rarely, clinical hepatitis.

44. Ketoconazole • It is the first orally effective broad-spectrum antifungal drug, useful in both dermatophytosis and deep mycosis. • Ketoconazole is less selective for fungal P450 than are the Fluconazole and Itraconazole (inhibit mammalian cytochrome P450 enzymes). • The usual dose is 200mg o.d or BD, higher doses are some times required. • Available 2% shampoo, cream, lotion.

45. Clinical use • it has limited use because of the drug interactions, endocrine side effects, and of its narrow therapeutic range. Oral formulation that is best absorbed at a low gastric pH. Ketoconazole is used in treatment of mucocutaneous candidiasis and non-meningeal coccidioidomycosis. It is also used in the treatment of seborrheic dermatitis and pityriasis versicolor (Topical/ shampoo).

46. Adverse effects • First, ketoconazole inhibition of human cytochrome P450 enzymes interferes with biosynthesis of adrenal and gonadal steroid hormones, producing significant endocrine effects such as gynecomastia, infertility, and menstrual irregularities.

47. Drug interactions • Second, the interaction with P450 enzymes can alter the metabolism of other drugs, leading to enhance toxicity of those agents: • Phenytoin 6. Nifedipine • Diazepam 7. cyclosporine • Haloperidol 8. Statins • Warfarin 9. protease inhibitors • Digoxin • Ketoconazole rises the blood concentration levels.

48. Ketoconazole side effects • ID/CC: A 23 year old marathon runner visits his sports medicine doctor complaining of unsightly, embarrassing growth of his right breast (GYNECOMASTIA) as well as undue fatigue after training and a slight yellowish hue in the eyes (JAUNDICE).

49. Continue • HPI: Three months ago, he was put on daily oral Ketoconazole because of he had been suffering from a severe, refractory tinea corporis infection. • PE: VS: bradycardia; fever (38.1 centigrade). PE: slight jaundice in conjunctiva, no lymphadenopathy, no neck masses, cardiopulmonary exam normal; no hepatomegaly; examination of skin reveals tinea corporis covering intertriginous areas, buttocks and scrotum.

50. Continue • Labs: AST and ALT increased, serum bilirubin level increased. • Imaging: US, liver: mildly enlarged liver. • Treatment: Discontinue drug; substitute treatment with alternative antifungal (e.g terbinafine).