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Antifungal drugs

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brief introduction about drugs used in fungal infections.

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Antifungal drugs

  1. 1. ANTIFUNGAL DRUGS PRESENTED BY: PARTH KHANDHERIA M.PHARM SEM-1 DEPARTMENT OF PHARMACOLOGY L.M. COLLEGE OF PHARMACY AHMEDABAD. 1
  2. 2. 01/22/16 CONTENTS  Introduction to fungi  Fungal infection  Antifungal drugs -Classification -M/A -Pharmacokinetics -Therapeutic use -Adverse effects -Drug Interaction  Antifungal screening
  3. 3. 01/22/16  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.
  4. 4. 01/22/16 Fungi can be divided into four classes 1. Yeasts 2. Yeast-like fungi 3. Dimorphic fungi 4. Moulds
  5. 5. 01/22/16 Type Characteristics Causitive Fungi Cause Yeasts reproduce by budding Cryptococcus neoformans meningitis Yeast-like fungi which partly grows like yeast and partly as filaments called hyphae Candida albicans oral/ vaginal thrush and systemic candidiasis. Dimorphic fungi which can grow as filaments or as yeast Histoplasma capsulatum systemic infections Moulds (Dermatophytes) filamentous fungi which reproduce by forming spores trichophyton sp Microsporum sp Epidermophyton sp skin or nail infections called tines or `ringworm'
  6. 6. 01/22/16 Factors aiding the spread of fungal disease  Action of immunosuppressant drugs  Acquired immunodeficiency syndrome (AIDS)  Broad-spectrum antibiotics  Chemotherapy agents
  7. 7. 01/22/16 OVERVIEW OF FUNGAL INFECTION Fungi that can cause infections live -In association with humans commensally, -In Environment  Fungal infections are termed as MYCOSES  In the UK, the commonest fungal disease is systemic Candidiasis
  8. 8. 01/22/16 Clinical classification of Mycoses: I. Cutaneous mycoses- These diseases are restricted to the keratinized layers of the skin, hair, and nails. II.Subcutaneous mycoses-It involve the dermis, subcutaneous tissues, muscle.These infections are difficult to treat and may require surgical interventions such as debridement. III Systemic mycoses due to opportunistic pathogens- Systemic mycoses due to opportunistic pathogens are infections of patients with immune deficiencies who would otherwise not be infected. IV Systemic mycoses due to primary pathogens- originate primarily in the lungs and may spread to many organ systems
  9. 9. 01/22/16 CUTANEOUS SUBCUTANEOUS OPPORTUNISTIC SYSTEMIC Superficial mycoses Tinea Piedra Candidiasis Chromoblastomycosis Sporotrichosis Mycetoma (eumycotic) Aspergillosis Candidiasis Cryptococcosis Geotrichosis Aspergillosis Blastomycosis Candidiasis Dermatophytosis Zygomycosis Fusariosis Trichosporonosis Histoplasmosis Cryptococcosis Geotrichosis Zygomycosis Fusariosis Trichosporonosis
  10. 10. 01/22/16 Classification of antifungal drugs based on M/A  Inhibition of fungal cell wall synthesis (Echinocandins): Caspofungin, Micafungin & Anidulafungin Bind to fungal cell membrane ergosterol and increase membrane permeability: (Polyene Group) Amphotericin-B.Nystatin  Inhibition of ergosterol+lanosterol synthesis (Allylamine Group) Terbinafine Inhibition of ergosterol synthesis:(Triazole Group) Inhibition of nucleic acid synthesis:5-Flucytosine Disruption of mitotic spindle and inhibition of fungal mitosis :Griseofulvin Miscellaneous: Topical Agents Ciclopirox, Tolnaftate, Naftifine, Butenafine and Topical Azoles
  11. 11. 01/22/16 Targets for antifungal therapy 11 Cell membrane Polyenes , Azoles , Allylamines Morpholines DNA synthesis E.g-Flucytosin Griseofulvin Cell wall E.g-Echinocandins
  12. 12. 01/22/16 M/A of Antifungal drugs
  13. 13. 01/22/16 Chemical Classification of antifungal drugs 1. Antibiotics a)Polyenes: Amphotericin B(AMB),Nystatin, Hamycin, Natamycin (Pimaricin) b) Heterocyclic benzofuran: Griseofulvin 2. Antimetabolite: Flucytosine(5-FC) 3. Azoles: a) Imidazoles (topical):Econazole, Miconazole,Clotrimazole,Oxiconazole, Ketonazole(Systemic) b)Triazoles (systemic):Fluconazole, Itraconazole, Voriconazole 4. Allylamine: Terbinafine 5. Other topical agent:Tolnaftate, Undecylenic acid, Benzoic acid, Quiniodochlor, Ciclopirox olamine, Butenafine, Sod. thiosulfate.
  14. 14. 01/22/16 Classification of antifungal drugs based on treatment  Drugs used to treat systemic fungal infection 1.Triazoles 2.Amphotericin-B 3.Ketoconazole(Imidazole) 4.Echinocandis 5.Flucytosine(5-FC)  Drugs given systemically for treating Superficial infections 1.Griseofulvin 2.Terbinafine  Topically used Antifungal drugs -Nystatin -Clotrimazole,Miconazole,Butaconazole,Sertaconazole,Oxiconazole -Ciclopirox -Benzoic acid & Sodium Thiosulphate
  15. 15. 01/22/16 Echinocandins  Three echinocandins are in current use: caspofungin, micafungin and anidulafungin  M/A- They cause fungal cell wall lysis by inhibiting the synthesis of 1,3-β-glucan, an essential component of the cell wall of susceptible fungi  Therapeutic Use- -Treatment of invasive Aspergillus infection  Pharmacokinetics- Caspofungin is orally not absorbed and hence infused slowly
  16. 16. 01/22/16  Adverse Effects: -Thrombophlebitis -Abnormal liver function -sensation of warmth, flushing,headache & rashes  Drug Interactions: - A combination of caspofungin with cyclosporine should be avoided because of the risk of hepatotoxicity. - Enzyme inducers increase the clearance of caspofungin while caspofungin increases the clearance of tacrolimus.
  17. 17. 01/22/16 1. Antibiotics A)Amphotericin-B (Polyene Group)  Chemistry & M/A - 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. -The polyenes have high affinity for ergosterol present in fungal cell membrane: combine with it, get inserted into the membrane. -alters the permeability of the fungal cell membrane by forming pores (channels) through which K+ . Na+ . H+ and other macromolecules leak out, leading to cell death
  18. 18. 01/22/16
  19. 19. 01/22/16  Resistance: Resistance to amphotericin-B is associated with a replacement of ergosterol by other sterols in fungal plasma membrane.  Pharmacokinetics: - It is poorly absorbed from GIT -Oral administration is thus effective only against fungal infections of intestine -Not for treatment of systemic fungal infections - Insoluble in water - Therefore prepared as a colloidal suspension with sodium desoxycholate for I.V. infusion.
  20. 20. 01/22/16  Antifungal spectrum & Therapeutic uses: -Yeast group and some mould group of fungal infections -To treat superficial candidiasis -Treatment of invasive aspergillosis -Mucormycosis (an opportunistic fungal infection in lungs) -Rapidly progressive blastomycosis , Histoplasmosis. - Non-AIDS cryptococcal meningitis (used with fluconazole or with flucytosine)  Adverse effects : - Acute toxicity- chills, fever, vomiting and modest hypotension - Long term toxicity- Hypochromic normocytic anaemia, nephrotoxicity - Intrathecal administration may lead to seizures - Hepatic impairment with jaundice
  21. 21. 01/22/16 Preparations 21 Trade name Shape of particles Type of lipid formulation Generic Name AmBisome Spheres Has complex liposomal mixture Liposomal Amphotericin B (L-AmB) Amphotec Disks Has cholesteryl sulfate Amphotericin B Colloidal Dispersion (ABCD) Abelcet Ribbons Has two phospholipids Amphotericin B Lipid Complex (ABLC)
  22. 22. 01/22/16 Nystatin (fungicidin)  Similar to amphotericin B but more toxic than amphotericin-b • Used only for superficial candidiasis of Skin, Mouth, Vagina, Intestine  Available as tablets and ointments (1 to 5 lacs U) – also vaginal tablets 22
  23. 23. 01/22/16 Other polyenes 23 Hamycin:  Water soluble  Absorption from GIT not reliable  Not used for systemic fungal infections  Used topically for Aspergillus, Candida, Monilial, Trichomonas vaginalis infections Natamycin:  Broad spectrum  Used topically for – Keratitis, Monilial infections, Trichomonas vaginalis
  24. 24. 01/22/16 b)Heterocyclic benzofuran Griseofulvin  Extracted from Penicillium griseofulvum  Active against most dermatophytes,including Epidermophyton , Trichophyton , Microsporum but not against Candida & other fungi causing deep mycosis  M/A- Disruption of the mitotic spindle & eventually arrests fungal mitosis at metaphase.  It also binds io newly synthesised keratin making it resistant to fungal invasion.
  25. 25. 01/22/16  Pharmacokinetics -Ineffective topically -Administered orally but it is variably absorbed from GIT -Micronisation of the drug particles and ingestion with a fatty meal improves its bioavailability.  Therapeutic Uses - in the systemic treatment of dermatophytosis -Terbinafin & azoles are more eficacious  Adverse effects & Interactions: -Headache, nausea, vomiting. photosensitivity and peripheral neuritis -As an inducer of cytochrome P-450 it can decrease the effectiveness of warfarin and oral contraceptives. -It causes disulfiram-like reaction with ethanol
  26. 26. 01/22/16 2. Antimetabolite: Flucytosine(5-FC)  5-FC is a fluorinated analogue of cytosine and is structurally related to the antineoplastic agent 5 fluorouracil.  Mechanism of Action: - Flucytosine is transported into the fungal cells with the help of cytosine permease enzyme - Where it is converted to 5- fluorouracil by the fungal cytosine deaminase enzyme - 5-FC is then further metabolised to 5- fluorodeoxyuridine monophosphate -Which is competitive inhibitor of thymidylate synthetase -blocks the formation of thymidine monophosphate from Deoxyuridine monophosphate - inhibits the fungal DNA synthesis
  27. 27. 01/22/16
  28. 28. 01/22/16 Pharmacokinetics Therapeutic Uses: Adverse Effects: -orally well absorbed -plasma half-life of 3-6 hrs -Levels rise rapidly in renal impairment leading to toxicity. -used as a part of combination therapy for candidiasis & cryptococcal meningitis(with amphotericin-B) or for chromoblastomycosis (with itraconazole). -in monotherapy, resistance and therapeutic failure are common -Bone marrow depression leading to leukopenia & thrombocytopenia -An elevation of hepatic enzymes and reversible hepatomegaly -Nausea, vomiting, epigastric distress and skin rash
  29. 29. 01/22/16 3. Azoles:  Imidazoles: - Topical: Clotrimazole, econazole,miconazole, tioconazole, sulconazole - Systemic: Ketoconazole  Triazoles: - Fluconazole, itraconazole and voriconazole
  30. 30. 01/22/16  Fungistatic or fungicidal properties depending upon drug concentration  Azoles can be divided into two groups: the imidazole group (2 nitrogen in the azole ring) & triazole group(3 nitrogens in the azole ring).  M/A- -bind to the fungal cytochrome P-450 dependent 14-α demethylase enzyme -that is responsible for the demethylation of lanosterol to ergosterol synthesis, -The ergosterol synthesis is therefore hindered. which results in damaged leaky fungal cell membrane.
  31. 31. 01/22/16 Acetyl CoA Squalene Lanosterol (ergosterol) Allylamine drugs Azoles Squalene-2,3 oxide Squalene epoxidase 14-α-demethylase 31 LanosterolLanosterol rol Squalene Squalene epoxide
  32. 32. 01/22/16 Ketoconazole  Pharmacokinetics: -Acidic pH required for the absorption of Ketoconazole. - bioavailability is reduced in achlorhydria. Such patients should be given acidifying agents (like orange juice) before ketoconazole administration. -Plasma half-life is 8-10hours - penetration into CSF is negligible; hence it is ineffective in the treatment of fungal meningitis  Therapeutic Uses: -Histoplasmosis - coccidioidomycosis - non -CNS blastomycosis
  33. 33. 01/22/16  Adverse Effects: -Nausea, vomiting and anorexia occur commonly but these adverse effects can be minimized by taking ketoconazole with food -Allergic dermatitis -Reversible elevations in liver enzymes - inhibits the synthesis of testosterone and estradiol which may lead to gynaecomastia and irregular menstrual cycles  Drug Interactions: -Ketoconazole inhibit mammalian cytochrome P450 (CYP3A4) more than fungal cytochrome P450. 1. Increases the serum concentrations of cisapride, terfenadine, astemizole and quinidine, warfarin, cyclosporine, tacrolimus, HMG-CoA reductase inhibitors 2. Rifampicin and phenytoin accelerate ketoconazole metabolism and reduce its efficacy -H2 receptor blockers, proton pump inhibitors and antacids decrease ketoconazole absorption by decreasing gastric acidity
  34. 34. 01/22/16 Triazole Drug Fluconazole Itraconazole Pharmacokinetic -Does not need acidic pH for its absorption from GIT -The half-life is 27-37 hrs - Dosage reductions are required in the presence of renal insufficiency. -Administeretion-oral , parenteral - requires low gastric pH for its absorption -highly protein bound (99%) - Oral bioavailability is variable - metabolised in liver & excreted in bile -Half-life-30-35 hrs. - more specific for fungal cytochrome P450 Therapeutic uses -Vulvovaginal candidiasis -Oropharyngeal candidiasis -Mucocutaneous candidiasis -Systemic candidiasis -Fungal meningitis -Histoplasmosis -non-meningeal blastomycosis -cutaneous and extracutaneous sporotrichosis - oropharyngeal & cutaneous candidlase -Ringworm,Fungal nail infection Adverse Efeect -nausea,vomiting,diarrhoea, headache -Increase in serum transaminase -HyPokalaemia. hypertension & oedema -Transaminase enzyme level may rise Drug interaction least effect on mammalian Same as Ketoconazole
  35. 35. 01/22/16 Voriconazole Pharmacokinetics: 2nd second generation triazole that has some distinguishing features -High oral bioavailability (96%) - Low protein binding (55%) -Good CSF penetration -Plasma half-life is only 6 hrs  Therapeutic Use: -Invasive aspergiliosis -Esophageal candidiasis
  36. 36. 01/22/16  Adverse effect: - visual changes such as blurred vision, altered colour perception and photophobia. -Nausea -Elevated Hepatic Enzyme  Drug Interactions: - Rifampicin.ritabutin.phenytoin end ritonavir accelerate voriconazole metabolism and reduce its efficacy. - Metabolism of Tacrolimus, cyclosporine and warfarin is retarded by Voriconazole
  37. 37. 01/22/16 4. Allylamine: Terbinafine(fungicidal)  M/A -squalene epoxidase converts squalene to lanosterol -Terbinafine inhibits fungal enzyme squalene epoxidase - Leads to reduction in lanosterol production that decreases ergosterol production which affects fungal cell membrane integrity and function.  Pharmacokinetics: - highly lipophilic and keratophilic resulting in high concentrations in stratum corneum,sebum, hair and nails. -A prolonged terminal half-life of about 15 days because of the very slow release of the drug from skin, nails and adipose tissue.
  38. 38. 01/22/16  Therapeutic Uses: -It can be used systemically as well as topically. - Orally it is specifically used to treat onychomycosis - Unlabeled use includes topical treatment of cutaneous candidiasis  Adverse Effects: -Headache - GIT upset - Liver enzymes elevation -Hepatobiliary dysfunction (but rarely)
  39. 39. Antifungal screening  The purpose of antifungal screening is not to define the therapeutic properties of an individual compound, but rather to indicate which of a large number of compounds or samples are worthy of further study. 41
  40. 40. Types of Screening A. General in vitro screens Agar dilution, Agar diffusion, Broth dilution B. Selective screening Cell wall synthesis in Candida albicans, Protoplast regeneration in Neurospora crassa, Morphology screens, Ergosterol biosynthesis C. In vivo screening Mouse Protection test, Multiple Infection model 42
  41. 41. References  Pharmacology by Rang H.P, Dale M.M, 6th edition,2007  Tripathi K.D, Essentials of Medical Pharmacology, 6th Edition, Jaypee brother publisher, New Delhi,  HL Sharma, KK Sharma, Principal of Pharmacology, 1st edition,2010
  42. 42. 01/22/16

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