antifungal slid.pharmacology junaid.pptx

Antifungal fungal drugs classification and mechanism of action of different antifungal drugs

1. ANTIFUNGALS Prepared by ; Junaid Iqbal Department of pharmacy,UOP

2. In this chapter Subcutaneous/ Systemic Drugs Amphotericin B Flucocytosine Ketoconazole Echinocandin ( Caspofungin ) Cutaneous Drugs Terbinafine Griesofulvin

3. Introduction Human fungal infection have increased dramatically in incidence and severity in recent years due to mainly advances in surgery, cancer treatment and critical care accompained by increase in use of broad spectrum antimicrobial and HIV. Infectious diseases caused by fungi are called mycoses and they are often chronic in nature. Some mycotic infections are superficial and some involve skin but fungi may penetrate into skin causing sub cutaneous infections. The fungal infection that are most difficult to treat are systemic mycoses, which are often life threatening.

4. Unlike bacteria, fungi are eukaryotic. They have rigid cell walls composed of largely of chitin rather than peptidoglycan. The fungal cell membrane contain ergosterol rather than cholesterol found in mammalian membrane. These Chemical characteristic are in targeting chemotherapeutic agents against fungal infections. Fungal infections are generally resistant to antibiotics used in treatment of bacterial infection and conversely bacteria are resistant to antifungal agents.

5. Classification of Antifungal Drugs Drugs for Sub cutaneous and systemic mycoses: Amphotericin B Andidulafungin Caspofungin Fluconazole Flucocytosine Itraconazole Ketoconazole Micafungin Posaconazole voriconazole

6. Classification of Antifungal Drugs 2. Drugs for cutaneous Mycoses: Butenafine Clotrimazole Ciclopirox Ecoconazole Greisofulvin Micoconazole Naftifine Nystatin Oxiconazole Sertaconazole Sulconazole Terbinafine Terconazole Tioconazole tolnaftate

7. Drugs for subcutaneous and systemic mycotic infection

8. 1. Amphotericin B Amphotericin A is not clinically use Amphotericin B is a naturally occurring polyene macrolide antibiotic produced by streptomyces nodosus . Inspite of its toxicity, Amphotericin B is a drug of choice for treatment of systemic mycoses.

9. Mechanism of action Several amphotericin B molecule bind to ergosterol in plasma membrane of sensitive fungal cell they form pores (channels) that require hydrophobic interactions between lipophilic segment of polyene antibiotic and the sterol. The protein disrupts membrane function, allowing electrolytes ( particularly postassium ) and small molecules to leak from cell, resulting in cell death.

10. PHARMACOLOGY OF AMPHOTERICIN B Chemistry - Amphotericin B is a polyene antibiotic ( polyene : containing many double bonds) Mechanism of action -Binding to ergosterol present in the membranes of fungal cells  Formation of “pores” in the membrane  Leaking of small molecules (mainly K+) from the cells -The ultimate effect may be fungicidal or fungistatic depending on the organism and on drug concentration.

11. Antifungal Spectrum Amphotericin B is either fungicidal or fungistatic depending upon the on the organism and concentration of drug. It is effective against a wide range of fungi including: Candida albican Histoplama capsulatum Cryptococcus neroforman Aspergillus

12. Pharmacokinetic Amphotericin B is administered by slow, Iv infusion. The most dangerous intrathecal route is chosen for treatment of meningitis caused by fungi that are sensitive to drug Amphotericin B has also been formulated with a variety of artificial lipids that form liposome Amphotericin B is extensively bound to plasma proteins and is distributed throughout the body becoming highly bound tissue.

13. Low level of drug and its metabolite appear in urine over a long period of time and some are also eliminated via bile. To avoid nephrotoxicity, alternatives including sodium loading with infusion of normal saline and lipid base amphotericin B products are used.

14. Adverse Effects Amphotericin B has low therapeutic index. Fever and Chills: These occurs most commonly 1 to 3 hr after starting IV administration but they are usually subside with repeated administration Renal Impairment: Despite the low level of drug excrete in urine patient may exhibit a decrease in glomerular filtration rate. Creatanine clearance can drop and K and Mg can are lost.

15. 3. Hypotension: A shock life fall in blood pressure accompained by hypokalemia may occur, require potassium supplimentation 4. Anemia can occur 5. Neurologic Effects can be seen with intrathecal administration of drug. 6. Thrombophlebitis

16. Liposomal preparations of amphotericin B Amphotericin B is packaged in a lipid- associated delivery system to reduce binding to human cell membrane , so reducing : A. Nephrotoxicity B. Infusion toxicity Also, more effective More expensive

17. 2. Flucytosine (5-FC) Flucytosine is a synthetic pyrimidine antimetabolite that is often use in combination with amphotericin B.

18. Mechanism of action 5 F-C ( flucytosine ) is taken by fungal cells via enzyme cytosine premase It is converted intracellulary first to 5 FU and then to 5- fluorodeoxyuridine monophosphate (F- dUMP ) and fluorouridine triphosphate (FUTP) which inhibits DNA & RNA synthesis respectively Human cells are unable to convert parent drug into its active metabolite

19. 3.Ketoconazole (AZOLE) Ketoconazole was first orally active azole available for treatment of systemic mycoses.

20. Mechanism of action Azoles are predominantly fungi static. They inhibit C-14 α - demethylase ( a cytochrome P450 enzyme) thereby blocking the demethylation of lanosterol to ergosterol . The principle sterol of fungal membrane. This inhibition disrupts membrane structure and function which in turn inhibits fungal cell growth. Azoles are relatively Non-toxic Most common adverse reaction is relatively minor gastrointestinal upset.

21. Drug Interaction & Contraindication All azoles have been reported to cause abnormalities in liver enzyme. By inhibiting cypP450, ketoconazole can potentiate the toxicities of other drugs such as cyclosporine and phenytoin and warfarin Ketoconazole and amphotericin B should not be use together because the decrease in ergosterol in fungal membrane reduce the fungicidal action of amphotericin B.

22. Contraindication Ketoconazole is teratogenicity in animals and is should not be given in pregnancy

23. Other Drugs Are: Fluconazole Itraconazole Voriconazole Posaconazole

24. Echinocandins Echinocandins are antifungal drugs that inhibit the synthesis of glucan in cell wall via inhibition of all enzyme 1,3 ß glucan synthase.

25. Caspofungin It is the first member of echocandins class of antifungal drugs. Caspofungin has activity against aspergillus and most candida species including those species that are resistant to azoles.

26. Adverse Effects include Fever Rash Nausea Phlebitis Flushing occur due to release of histamine from mast cell

27. Other drugs are: Micafungin Anidulafungin

28. Drugs for cutaneous mycotic Infection Mold like fungi that cause cutaneous skin infections are called dermatophytes or tinea . These tinea are classified by the site of their infection such as tinea pedis , which refers to an infection of feets .

29. Squalene Epioxidase Inhibitor These agents act by inhibiting squalene epioxide , resulting in blocking of biosynthesis of ergosterol , an essential component of fungal cell membrane. Drugs: Terbinafine Naftifine Butenafine

30. Terbinafine Oral terbinafine is a drug of choice for treating dermatophytoses especially onychomycoses (Nail infection) Terbinafine hydrochloride , also known under the trade name Lamisil ,is a synthetic allylamine antifungal developed by Novartis . It is highly hydrophobic in nature and tends to accumulate in skin, nails, and fatty tissues.

31. Mechanism of Action Like Azole drugs, it interfere with ergosterol biosynthesis but rather than interacting with P450 system, terbinafine inhibits the fungal enzyme squalene epioxide . This leads to accumulation of sterol squalene which is toxic to organism. Squalene epioxide is the enzyme that govern the conversion of squalene into ergosterol ( the major component of fungal cell membrane). If squalene epioxide is inhibited it will not converted to ergosterol and hence squalene starts accumulating in fungal cell, which leads to fungal cell death.

32. Antifungal Spectrum The drug is primarily fungicidal. Topical terbinafie 1% cream and soultion are used to treat tinea pedis , tinea coporis ( Scalp), and tinea cruris ( groin area).

33. Griseofulvin Griseofulvin has been largely replaced by oral terbinafine for the treatment of dermatophytic infections of the nails, although it is still used for ring worm and dermatophytosis of the skin and hair.

34. Mechanism of action Griseofulvin mechanism of action at cellular level is unclear but it is deposited in newly forming skin where it binds to keratin, protecting skin from new infection. Since its action is to prevent infection of these new skin structures, it must be administered for 2-6 weeks for skin and hair infection to allow replacement of infected keratin by resistant structure. Nail infection may require therapy for months to allow regrowth of protected nail.

35. Other drugs are: Nystatin Imidazole include ( Butoconazole , Clotrimazole , Oxiconazole , Ecoconazole etc ) Ciclopirox Tolnaftate Nystatin worked as amphotericin B Imidazoles are topical azole. Ciclopirox inhibit transport of essential elements ( Disruption of RNA , DNA and protein synthesis) in fungal cell Tolnaftate distorts the hyphae and stunts mycelial growth in susceptible fungi