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Antifungal Slide 2 Antifungal agents: These drugs are used for superficial or deep systemic fungal infection. Fungal infection termed as mycoses. 2 Slide 3 FUNGI AND FUNGAL INFECTION: Fungi are Eukaryotic cells. They possess mitochondria, nuclei & cell membranes. They have rigid cell walls containing chitin as well as polysaccharides, and a cell membrane composed of ergosterol. While bacterial cells are prokaryotic. So, antibacterial agents can exhibit Selective toxicity. In contrast, similarity between fungal & mammalian cells makes Antifungal drugs non-selective. Thus, Antifungal drugs are in general more toxic than antibacterial agents. 3 Slide 4 Exampels of Fungi: Yeasts Molds Mushrooms Puffballs Shelf fungi Animal pathogen Plant pathogen 4 Slide 5 Clinically important fungi may be classified into four main types: 1.yeasts(cryptococcus neoformans) 2.yeast like fungi that produce a structure resembling a mycelium(candida albicans) 3.filamentous fungi with true mycelium(Aspergillus fumigatus) 4.Dimorphic fungi that,depending on nutritional consraints,may grow as either yeasts or filamentous fungi(histoplasma capsulatum) 5 Slide 6 1) Superficial fungal infections can be classified into 1.dermatomycoses: Infection of hair,skin,nails Most commonly caused by Trichophyton,Microsporum or Epidermophyton,giving rise to various types of ring worm or tine. 6 Slide 7 2.candidiasis: Yeast like organisam may infect the mucous membranes of the mouth or vagina(thrush) or the skin. 2) Systemic fungal infection: Blastomycosis,histoplasmosis,coccidiomycosis and paracoccidomycosis;thses are the primary infections. Involve the internal organs 7 Slide 8 Classification: 1) Antibiotics: Polyenes: - Amphotericin B(AMB) - Nystatin - Hamycin - Natamycin Heterocyclic benzofuran: - Griseofulvin 2) Antimetabolite: - Flucytosine(5-FC) 8 Slide 9 3) Azoles: a)imidazoles: Topical -Clotrimazole -Econazole -Miconazole systemic Ketoconazole b)Triazoles: systemic Fluconazole - Itraconazole 4) Allylamine: - Terbinafine - Naftifine - Butenafine 9 Slide 10 5) -glucan synthase inhibitors: -Caspofungin -Micafungin -Anidulafungin 6) Other topical agents: - Tolnaftate -Undecylenic acid -Benzoic acid -Quiniodochlor -Ciclopirox olamine -Sodium thiosulfate 10 Slide 11 Action of antifungal agents: 11 Slide 12 Polyenes, triazoles, and imidazoles target ergosterol destroying the cell membranes integrity. Allylamines inhibit ergosterol synthesis. flucytosine inhibit DNA/RNA synthesis. griseofulvin inhibit fungal cell mitosis preventing cell proliferation and function. 12 Slide 13 1.Antibiotics: A. Polyenes: 1. Amphotericin B(AMB): It is the drug of choice used in the treatment of the systemic mycoses although it is toxic. It is sometimes used in combination with flucytosine to decrease the toxicity of amphotericin B. 13 Slide 14 M/A: It binds with ergosterol(component of fungal cell membrane) AMB-ergosterol complex alter the membrane permeability creates pore in the membrane pores allows the leakage of inracellular ions,amino acid & micromolecules cell death 14 Slide 15 Pharmacokinetics: i.v.(t - 24 hours) mostly metabolized some is excreted by kidney does not readily pass the blood brain barrier extensively bound to plasma proteins, and is distributed throughout the body. However, amphotericin B does cross the placenta; some is also eliminated via the bile. Liposomal preparations of amphotericin B are available and have shown therapeutic efficacy. 15 Slide 16 Clinical use: topically applied for, oral,vaginal, cutaneous candidasis otomycosis leishmaniasis:it is a reserve drug for resistant cases of kala azar and mucocutaneous leishmaniasis. 16 Slide 17 Adverse effects: Infusion related: fever,chills,aches,nausea,vomiting and dyspnoea and can be alleviated partly by pretreatment with NSAIDs,antihistamines,meperidine and adrenal steroids. Dose dependent: Nephrotoxicity includes reduce g.f.r,acidosis, hypokalemia and inability to concentrate urine. anemia:it is due to bone marrow depression(decrease erythropoietin) CNS toxicity:occurs only on intrthecal injection headache,vomiting,nerve palsies. 17 Slide 18 Alternative Formulations to Decrease Toxicity 18 Slide 19 LIPID amphotericin B formulations in use Amphotericin B Lipid Complex: (ABLC; Abelcet) Amphotericin B Colloidal Dispersion: (ABCD; Amphocil or Amphotec) Liposomal Amphotericin B:(L-AMB; Ambisome) 19 Slide 20 2.Nystatin(fungicidin): It is similar in structure to amphotericin and same mechanism action. No absorption from the mucous membranes of the body or from skin use: Use limited to candida infection of skin,git,mucous membrane unwanted effects: nausea,vomiting,diarrhoea. 20 Slide 21 B. Hetrocyclic benzofuran: Griseofulvin: It is isolated from Penicillium griseofulvum and cure infections due to dermatophytes(ringworm) when administered orally. It is ineffective against candida albicans. M/A: It interacts with microtubules of miotic spindle and with cytoplasmic microtubules disorientation of miotic microtubules and interfere in the mitosis inhibit the growth of fungal hyphae. 21 Slide 22 It is very low water soluble drug,low absorption,absorption improved by taking with fatty meals and microfine the drug particles. Adverse effects: Headache,GIT disturbances,peripheral neuritis,rashes,leukopenia. Interaction: It induces warfarin metabolism and reduces efficacy of oral contaceptives. 22 Slide 23 2.Antimetabolite: Flucytosine(5-fc): It is pyrimidine analogue related to the chemotherapeutic agent 5-FU (5 Fluorouracil). M/A: This permeates the fungal cell wall and converts into 5-FU phosphorylation of 5-FU and formation of UDP and UTP which inhibits to thymidylate synthesis inhibitn the DNA and RNA synthesis inghibit fungal cell grpwth 23 Slide 24 Adverse effects: Bone marrow depression Leucopenia Rash Diarrhoea Hepatitis Use: In cyptococcosis its synergistic action with AMB is utillized to reduce the total dose of the more toxic latter dose. 24 Slide 25 3.Azoles : M/A: Inhibit the fungal cytochrome P450 enzyme lanosterol 14-methylase impair ergosterol synthesis membrane abnormalities in fungus. 25 Slide 26 Ketoconazol: Orally used for mucocutaneous candidiasis or dermatophytoses. Pharmacokinetics Variable oral absorption, dependent on pH (often given with cola or fruit juice) T1/2 = 7-10 hours Protein binding > 99% Hepatic, bile and kidney elimination 26 Slide 27 A/E: Decrease androgen production and displace testoterone from protein binding sites gynaecomastia,loss of libido and oligospermia. Menstrual irregularities in female. Dose-related inhibition of CYP P450. 27 Slide 28 Interaction: Potent inhibitor of cytochrome P450 3A4 Rifampin and phenytoin decrease ketoconazole levels Ketoconazole increases cyclosporin, warfarin and terfenadine levels. Drugs that increase gastric pH will decrease blood levels of ketoconazole Antacids, omeprazole, H2 blockers 28 Slide 29 Fluconazole: Fluconazole is clinically important because of its lack of the endocrine side effects of ketoconazole, and its excellent penetrability into the CSF & ocular fluids. Water soluble having wider range of activity than Ketoconazol Drug of choice in fungal meningitis Non-albicans Candida species more likely to exhibit primary resistance ItraconazoleL: Uses: Histoplasmosis Sporotrichosis (This fungal disease usually affects the skin, although other rare forms can affect the lungs, joints, bones, and even the brain). Aspergillosis Blastomycosis 29 Slide 30 30 Slide 31 local azoles Very popular local azoles are Clotrimazole, Econazole and Miconazole (For Tinea, Ring worm, Athletes foot, otomycosis, oral, cutaneous & vaginal candidiasis) Mechanism of action is same as that of Ketoconazole i.e. ergosterol inhibition by inhibiting CYP450 Clotrimazole is favoured in vaginitis because of long lasting residual effect and once daily dosing Miconazole causes frequently vaginal irritation & pelvic cramp. Available as lotion, cream, powder, vaginal tablet etc. 31 Slide 32 4.Allylamine: Terbinafine: M/A: inhibit the enzyme squalene epoxidase inhibit synhesis of ergosterol. Possible superior to greiseofluvin in onchomycoses. A/E: GI distress,rash,headache,possible hepatotoxicity. 32 Slide 33 5. -glucan synthase inhibitors: 1) Caspofungin Metabolized by hydrolysis and N-acetylation Not inhibitor/inducer/substrate of CYP Enzymes induced by carbamazepine, cyclosporine, dexamethasone, efavirenz, nelfinavir, nevirapine, phenytoin, rifampin 2) Micafungin: Substrate 3A4 minor; weak inhibitor of 3A4 Increased levels of nifedipine Increased monitoring for toxicity and dosage adjustment needed. 3) Anidulafungin: Not inhibitor/inducer/substrate of CYP Degrades at normal pH and condition to an open-ringed peptide 33 Slide 34 6.Other topical agents: All these drugs are used in dermatophytosis. 1) Tolnaftate: Effective drug fof tinea cruris and tinea corporis. It causes little irritation and is better than other topical agents. 2) Ciclopirox olamine: It used in tinea infections,pityriasis versicolor, dermal candidiasis and vaginal candidiasis. 3) Undecylenic acid: It used for tinea pedis,nappy rash and tinea cruris. Used in combination with its zinc salt. 34 Slide 35 4) Benzoic acid: Antifungal+Antibacterial Used in combination with salicyclic acid,its kerolytic action helps to remove the infected tissue and promotes the penetration of benzoic acidinto the lesion. 5) Quiniodochlor: Weak antifungal+antibacterial Used in dermatophytosis,mycosis barbae,seborrhoeic dermatitis, infected eczematricomonas vaginitis. 6) Sodium thiosulphate: It is effective in pityriasis versicolor. 35 Slide 36 Future Targets Moving into the cell: Aspartate pathway: Fungi must synthesize Met, Ile, Thr. Siderophore biosynthesis: Iron importation mechanism Fungi must scavenge for iron inside host Siderophores bind soluble iron with high affinity Actively transported through cell wall 36 Slide 37 Summary of Treatments Pathogen Primary Secondary Cryptococcus neoformansAmphotericin B + Flucytosine followed by Fluconazole Itraconazole or Amphotericin B Histoplasma capsulatumItraconazole or Amphotericin B Fluconazole MucomycosisAmphotericin BPosaconazole Sporothrix schenckiiAmphotericin B Itraconazole Saturate solution of potassium iodide 37 Slide 38 References: 1)Tripathi KD.Essentials of medical pharmacology,Jaypee brother medical publisher,5 th edition(2005),p.p:715-724 2)Rang H.P.,Dale M.M,Ritter J.M.,Flower R.J.,Churchill livingstone Elsevier,6 th edition(2007),p.p:692-697 3) Goodman and Gilman, The pharmacological basis of therapeutics, 11 th Edition,2008,p.p:800-811 38 Slide 39 39