Antifungaldrugs

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  • There are key differences between mammalian and fungal eukaryotic cells. This is the basis of drug selectivity.
  • Around 100 polyene antibiotics have been described, but few have been developed for clinical use. Amphotericin B was first isolated by Gold et al from Streptococcus nodosus in 1955. It is an amphoteric compound composed of a hydrophilic polyhydroxyl chain along one side and a lipophilic polyene hydrocarbon chain on the other. Amphotericin B is poorly soluble in water. It binds to sterols of susceptible fungal cells. Amphotericin B has a selective action, binding avidly to membranes of fungi and less avidly to mammalian cells. The relative specificity for fungi may be due to the drug’s greater avidity for ergosterol than for cholesterol. On binding to the fungal cell membranes, Amphotericin B interferes with permeability and transport functions. The drug is thought to form a pore in the membrane, the hydrophilic core of the molecule creating a transmembrane ion channel. One of the repercussions of this is a loss of intracellular potassium, magnesium, sugars and metabolites and then cellular death. Until the introduction of voriconazole, amphotericin B was the most broad spectrum intravenous antifungal available, although not always very potent.
  • Above are antifungals which target the cell membrane. First of all we will look at the azole family. These drugs are far less toxic than amphotericin B.
  • The azoles inhibit the fungal P450 enzymes responsible for the synthesis of ergosterol, the main sterol in the fungal cell membrane. The azoles act through an unhindered nitrogen, which binds to the iron atom of the heme, preventing the activation of oxygen which is necessary for the demethylation of lanosterol. In addition to the unhindered nitrogen, a second nitrogen in the azoles is thought to interact directly with the apoprotein of lanosterol demethylase. It is thought that the position of this second nitrogen in relation to the apoprotein may determine the specificity of different azole drugs for the enzyme. The resulting depletion of ergosterol alters the fluidity of the membrane and this interferes with the action of membrane-associated enzymes. The overall effect is an inhibition of replication (ie. the azoles are fungistatic drugs). A further repercussion is the inhibition of transformation of candidal yeast cells into hyphae-the invasive and pathogenic form of the parasite. Since no drug acts with complete specificity, it is not surprising that the azoles also have some effect on the closely related mammalian p450 enzymes. These are a large family of haem proteins. Hepatic p450 enzymes are involved in the detoxification of drugs whereas extrahepatic enzymes play an important part in several synthetic pathways including steroid biosynthesis in the adrenal gland.
  • The time taken for peak serum concentrations to be reached is 2-4 hrs. This is determined by several factors including: disintegration/dissolution rate (favoured by acidic pH?) Gastric emptying rate Intestinal transit time Intestinal metabolism (CYP 3A4 in intestinal wall) Rate of absorption from the intestine First Pass effect (metabolism in liver) Clearance rate. Food delays absorption, but does not decrease peak serum concentrations significantly.
  • Molecular mechanisms of azole resistance. In a susceptible cell, azole drugs enter the cell through an unknown mechanism, perhaps by passive diffusion. The azoles then inhibit lanosterol 14-  demethylase ( ERG11 ) (pink circle), blocking the formation of ergosterol. Two types of efflux pumps are expressed at low levels. The CDR proteins are ABC transporters (ABCT) with both a membrane pore (green tubes) and two ABC domains (green circles). The MDR protein is an Major Facilitator transport protein (MF) with a membrane pore (red tubes). ABC transporters use ATP as their energy source, whereas MF transporters use the proton motive force. In a “model” resistant cell, the azoles also enter the cell through an unknown mechanism. In a resistant cell, the azoles are blocked from interacting normally with the target enzyme because the enzyme can be modified. Lanosterol 14-  demethylase is encoded by the gene ERG11. Several genetic alterations have been identified that are associated with the ERG11 gene of C. albicans , including point mutations in the coding region, overexpression of the gene, gene amplification (which leads to overexpression) and gene conversion or mitotic recombination. Several different specific point mutations (dark slices in pink circles) have been identified by comparing azole-resistant clinical isolate with a sensitive isolate from a single strain of C. albicans. The first point mutation to be identified within ERG11 of a clinical isolate of C. albicans which altered the fluconazole sensitivity of the enzyme was discovered in 1997 by White et al. This mutation results in the replacement of arginine with lysine at amino acid 467 of the ERG11 gene (abbreviated R467K). Overexpression of ERG11 has been described in several different clinical isolates. In each case, the level of overexpression is not substantial (less than a factor of 5). It is difficult to assess the contribution of ERG11 overexpression to a resistant phenotype, since these limited cases of overexpression have always accompanied other alterations associated with resistance, including the R467K mutation, and overexpression of genes regulating efflux pumps. In addition to alterations in the lanosterol demethylase, a common mechanism of resistance is an alteration in other enzymes in the same biosynthetic pathway (dark slices in blue spheres). The sterol components of the plasma membrane are modified (darker orange of membrane). Finally, the azoles are removed from the cell by overexpression of the CDR genes (ABCT) and MDR (MF). The CDR pumps are effective against many azole drugs, while MDR appears to be specific for fluconazole. Overexpression of the transporters may be a result of gene amplification or increased gene transcription. The more efficient removal of the azoles means that the drugs never reach their therapeutic concentrations within the cell. For more detail read: White T.C., Marr K.A., Bowden R.A. Clinical Microbiology Reviews 1998 11 ; 382-402. Available on internet at aac.asm.org/.
  • Absorption: Oral absorption is almost complete (>90%) and unlike ketoconazole, absorption is not affected by food or intragastric pH. It has linear pharmacokinetics which means blood concentrations increase in proportion to dosage. Maximum serum concentrations increase to 2-3mg/l after repeated dosing with 50mg. Intravenous delivery of 400mg results in a max steady state concentration of 20 µg/ml. Distribution: Widely distributed achieving therapeutic concentrations in most tissues and body fluids. Concentrations in CSF are 50-60% of the simultaneous serum concentration in normal individuals and even higher in patients with meningitis. Therefore, it may become the drug of first choice for most types of fungal meningitis. Fungicidal concentrations are also achieved in vaginal tissue, saliva, skin and nails. Metabolism and excretion: Fluconazole has a half life of approx 24 hrs. More than 90% of a dose is eliminated in the urine: about 80% as an unchanged drug and 10% as inactive metabolites. The drug is cleared through glomerular filtration, but there is significant tubular reabsorption. The plasma half-life is prolonged in renal failure, necessitating adjustment of the dosage. Absorption: Oral absorption is almost complete (>90%) and unlike ketoconazole, absorption is not affected by food or intragastric pH. It has linear pharmacokinetics which means blood concentrations increase in proportion to dosage. Maximum serum concentrations increase to 2-3mg/l after repeated dosing with 50mg. Intravenous delivery of 400mg results in a max steady state concentration of 20 µg/ml. Distribution: Widely distributed achieving therapeutic concentrations in most tissues and body fluids. Concentrations in CSF are 50-60% of the simultaneous serum concentration in normal individuals and even higher in patients with meningitis. Therefore, it may become the drug of first choice for most types of fungal meningitis. Fungicidal concentrations are also achieved in vaginal tissue, saliva, skin and nails. Metabolism and excretion: Fluconazole has a half life of approx 24 hrs. More than 90% of a dose is eliminated in the urine: about 80% as an unchanged drug and 10% as inactive metabolites. The drug is cleared through glomerular filtration, but there is significant tubular reabsorption. The plasma half-life is prolonged in renal failure, necessitating adjustment of the dosage. Absorption: Oral absorption is almost complete (>90%) and unlike ketoconazole, absorption is not affected by food or intragastric pH. It has linear pharmacokinetics which means blood concentrations increase in proportion to dosage. Maximum serum concentrations increase to 2-3mg/l after repeated dosing with 50mg. Intravenous delivery of 400mg results in a max steady state concentration of 20 µg/ml. Distribution: Widely distributed achieving therapeutic concentrations in most tissues and body fluids. Concentrations in CSF are 50-60% of the simultaneous serum concentration in normal individuals and even higher in patients with meningitis. Therefore, it may become the drug of first choice for most types of fungal meningitis. Fungicidal concentrations are also achieved in vaginal tissue, saliva, skin and nails. Metabolism and excretion: Fluconazole has a half life of approx 24 hrs. More than 90% of a dose is eliminated in the urine: about 80% as an unchanged drug and 10% as inactive metabolites. The drug is cleared through glomerular filtration, but there is significant tubular reabsorption. The plasma half-life is prolonged in renal failure, necessitating adjustment of the dosage. Absorption: Oral absorption is almost complete (>90%) and unlike ketoconazole, absorption is not affected by food or intragastric pH. It has linear pharmacokinetics which means blood concentrations increase in proportion to dosage. Maximum serum concentrations increase to 2-3mg/l after repeated dosing with 50mg. Intravenous delivery of 400mg results in a max steady state concentration of 20 µg/ml. Distribution: Widely distributed achieving therapeutic concentrations in most tissues and body fluids. Concentrations in CSF are 50-60% of the simultaneous serum concentration in normal individuals and even higher in patients with meningitis. Therefore, it may become the drug of first choice for most types of fungal meningitis. Fungicidal concentrations are also achieved in vaginal tissue, saliva, skin and nails. Metabolism and excretion: Fluconazole has a half life of approx 24 hrs. More than 90% of a dose is eliminated in the urine: about 80% as an unchanged drug and 10% as inactive metabolites. The drug is cleared through glomerular filtration, but there is significant tubular reabsorption. The plasma half-life is prolonged in renal failure, necessitating adjustment of the dosage. Absorption: Oral absorption is almost complete (>90%) and unlike ketoconazole, absorption is not affected by food or intragastric pH. It has linear pharmacokinetics which means blood concentrations increase in proportion to dosage. Maximum serum concentrations increase to 2-3mg/l after repeated dosing with 50mg. Intravenous delivery of 400mg results in a max steady state concentration of 20 µg/ml. Distribution: Widely distributed achieving therapeutic concentrations in most tissues and body fluids. Concentrations in CSF are 50-60% of the simultaneous serum concentration in normal individuals and even higher in patients with meningitis. Therefore, it may become the drug of first choice for most types of fungal meningitis. Fungicidal concentrations are also achieved in vaginal tissue, saliva, skin and nails. Metabolism and excretion: Fluconazole has a half life of approx 24 hrs. More than 90% of a dose is eliminated in the urine: about 80% as an unchanged drug and 10% as inactive metabolites. The drug is cleared through glomerular filtration, but there is significant tubular reabsorption. The plasma half-life is prolonged in renal failure, necessitating adjustment of the dosage.
  • In most fungi, hyphae are the main mode of vegetative growth, and are collectively called a mycelium ; yeasts are unicellular fungi that do not grow as hyphae.
  • Antifungaldrugs

    1. 1. R.GAYATHRI DEVI PHARM D Antifungal Drugs
    2. 2. Introduction - Also called antimycotic drugs <ul><li>Used to treat two types of fungal infection: </li></ul><ul><ul><li>Superficial fungal infections - skin or mucous membrane </li></ul></ul><ul><ul><li>Systemic fungal infections - lungs or central nervous system </li></ul></ul><ul><li>Fungi causing mycosis live as commensally or are present in the environment. </li></ul><ul><li>Earlier superficial infections were common and systemic rather rare. </li></ul><ul><li>Recently there is increase in local as well as systemic fungal infections. </li></ul><ul><li>Reason for this is opportunistic infections </li></ul>
    3. 3. Opportunistic infections <ul><li>Immuno-suppression due to </li></ul><ul><ul><li>- Cancer chemotherapy </li></ul></ul><ul><ul><li>- AIDS </li></ul></ul><ul><ul><li>Corticosteroid overuse </li></ul></ul><ul><li>Indiscriminate use of broad spectrum antibiotics </li></ul>
    4. 4. Fungal infections <ul><li>Superficial </li></ul><ul><ul><li>Skin </li></ul></ul><ul><ul><li>Hair </li></ul></ul><ul><ul><li>Nails </li></ul></ul><ul><ul><li>Mucous membrane </li></ul></ul><ul><li>Deep </li></ul><ul><ul><li>Tissues (muscle & connective tissue) </li></ul></ul><ul><ul><li>Organs </li></ul></ul>Images of some superficial skin infections
    5. 5. Types of fungal infections - Mycoses <ul><li>Superficial mycoses </li></ul><ul><ul><li>Affect the skin, hair and nails – ringworm/tinea or onychomycosis </li></ul></ul><ul><li>Subcutaneous mycoses (tropical) </li></ul><ul><ul><li>Affect the muscle and connective tissue immediately below the skin </li></ul></ul><ul><li>Systemic (invasive) mycoses </li></ul><ul><ul><li>Involve the internal organs </li></ul></ul><ul><li>Allergic mycoses </li></ul><ul><ul><li>Affect lungs or sinuses </li></ul></ul><ul><ul><li>Patients may have chronic asthma, cystic fibrosis or sinusitis </li></ul></ul>There is some overlap between these groups
    6. 6. MOST COMMON FUNGAL PATHOGENS <ul><li>Dermatophytes – Microsporum, Epidermophyton and Trichophyton </li></ul><ul><li>Candida – C. albicans, C. glabrata, C. tropicalis </li></ul><ul><li>Aspergillus </li></ul><ul><li>Cryptococcus </li></ul><ul><li>Rhizopus </li></ul>
    7. 7. Causative fungi <ul><li>Superficial infections by </li></ul><ul><ul><li>Dermatophytes (ring worms): athlete`s foot or tinea pedis, jock itch or tinea cruris, tinea capitis etc. </li></ul></ul><ul><ul><li>Candida: oral thrush, vaginitis and diaper candidiasis etc. </li></ul></ul><ul><li>Deep infections are </li></ul><ul><ul><li>Candidiasis: Chronic mucocutaneous candidiasis, systemic candidiasis etc. </li></ul></ul><ul><ul><li>Aspergillosis: broncho-pulmonary aspergillosis </li></ul></ul><ul><ul><li>Coccidiomycosis: pulmonary and disseminated (complications – pneumonia) </li></ul></ul><ul><ul><li>Histoplasmosis: H. capsulatum (common in HIV) </li></ul></ul>
    8. 8. What are the targets for antifungal therapy? Cell membrane Fungi use principally ergosterol instead of cholesterol Cell Wall Unlike mammalian cells, fungi have a cell wall DNA Synthesis Some compounds may be selectively activated by fungi, arresting DNA synthesis.
    9. 9. Polyene antibiotics- Amphotericin B <ul><li>Fermentation product of Streptomyces nodusus </li></ul><ul><li>High affinity for ergosterol present in fungal cell membrane </li></ul><ul><li>Hydrophilic polyhydroxyl chain along one side and a lipophilic polyene hydrocarbon chain on the other </li></ul><ul><li>Binds sterols in fungal cell membrane – </li></ul><ul><ul><li>high affinity for ergosterol present in fungal cell membrane </li></ul></ul><ul><ul><li>affinity is less for host cell membrane although closely resembles </li></ul></ul><ul><li>Creates transmembrane channel and electrolyte leakage. </li></ul><ul><li>Active against most fungi except Aspergillus terreus , Scedosporium spp . </li></ul><ul><li>Bacteria lack sterols so insensitive to polyenes </li></ul>
    10. 10. Cell Membrane Active Antifungal <ul><li>Cell membrane </li></ul><ul><li>1. Polyene antibiotics </li></ul><ul><li>- Amphotericin B, lipid formulations </li></ul><ul><li>- Nystatin (topical) </li></ul><ul><li>2. Azole antifungals </li></ul><ul><li>Imidazoles: </li></ul><ul><ul><li>Topical: Clotrimazole, econazole, miconazole </li></ul></ul><ul><ul><li>Systemic: Ketoconazole </li></ul></ul><ul><li>Triazoles: Fluconazole, itraconazole and voriconazole </li></ul>
    11. 11. Antifungal spectrum <ul><li>Most Toxic antifungal </li></ul><ul><li>Fungicide at high and static at low conc. </li></ul><ul><li>Effective against </li></ul><ul><ul><li>Candida albicans </li></ul></ul><ul><ul><li>Histoplasma capsulatum </li></ul></ul><ul><ul><li>Cryptococcus </li></ul></ul>
    12. 12. Pharmacokinetics <ul><li>Insoluble in water </li></ul><ul><li>Unstable at 37degree </li></ul><ul><li>Poorly absorbed from GIT </li></ul><ul><li>Cannot cross BBB </li></ul><ul><li>Highly bound to plasma proteins </li></ul><ul><li>Takes 2 months for complete clearance of drug </li></ul><ul><li>Given as I/V infusion </li></ul><ul><li>For fungal meningitis given intrathecally </li></ul><ul><li>Has immuno-stimulant action also </li></ul><ul><li>Given in immuno-compromised patients for fungal infections </li></ul>
    13. 13. Uses <ul><li>Broad spectrum antifungal </li></ul><ul><li>Useful for </li></ul><ul><li>1. Candida that causes </li></ul><ul><ul><li>oral </li></ul></ul><ul><ul><li>vaginal </li></ul></ul><ul><ul><li>cutaneous candidiasis </li></ul></ul><ul><li>2. Cryptococcus </li></ul><ul><li>3. Histoplasma </li></ul><ul><li>4. Aspergillosis </li></ul><ul><li>5. Also effective for Leishmaniasis(Reserve drug for resistant cases of Kala Azar) </li></ul>
    14. 14. ADRs <ul><li>Acute reactions - occurs with each infusion </li></ul><ul><ul><li>Chills, Nausea, Vomiting, Pain, Fever, Aches, Dyspnoea </li></ul></ul><ul><ul><li>So corticosteroids are administered along with the drug </li></ul></ul><ul><li>Thrombophlebitis </li></ul><ul><li>Bone marrow depression - Reversible anemia </li></ul><ul><li>On intrathecal injection – Headache, Vomiting, Nerve paralysis </li></ul><ul><li>Renal toxicity leading to – Azotemia, Decreased GFR, Acidosis, Hypokalemia, Inability to conc. urine </li></ul>
    15. 15. Newer Amphotericin B <ul><li>They are developed to overcome </li></ul><ul><li>1. Side effects </li></ul><ul><li>2. To improve tolerability </li></ul><ul><li>3. To get the drug at site of action </li></ul><ul><li>4. To reduce the toxicity i.e.. Less nephrotoxic and minimal anemia </li></ul><ul><li>Formulations are: </li></ul><ul><li>1. Amphotericin B lipid complex </li></ul><ul><li>2. Amphotericin B colloidal dispersion </li></ul><ul><li>3. Liposomal Amphotericin B </li></ul><ul><li>(Only drawback of these formulations is less efficacy) </li></ul>
    16. 16. Drug Interactions of Amphotericin B <ul><li>With Flucytocin-synergistic action </li></ul><ul><li>Rifampicin and Minocyclin – </li></ul><ul><ul><li>Both potentiate Amphotericin B </li></ul></ul><ul><li>Vancomycin and Aminoglycoside – </li></ul><ul><ul><li>Both increase risk of nephrotoxicity </li></ul></ul><ul><li>Preparation and doses: </li></ul><ul><ul><li>50 – 100 mg four times a day orally </li></ul></ul><ul><ul><li>3% ear drops </li></ul></ul><ul><ul><li>Systemic: 50 mg vial (one vial diluted in 500 ml of 5% glucose and initially 1 mg test dose followed by infusion for 4 – 8 Hrs) </li></ul></ul>
    17. 17. Nystatin <ul><li>Similar to Amphotericin B but more toxic than Amphotericin B </li></ul><ul><li>Used only for superficial candidiasis of </li></ul><ul><li>Skin, Mouth, Vagina, Intestine </li></ul><ul><li>As ointment ,oral tablets & suppositories </li></ul><ul><li>Available as tablets and ointments (1 to 5 lacs U) – also vaginal tablets </li></ul><ul><li>Orally not absorbed but can be used in monilial diarrhoea </li></ul>
    18. 18. Other Polyenes <ul><li>Hamycin: </li></ul><ul><li>Water soluble </li></ul><ul><li>Absorption from GIT not reliable </li></ul><ul><li>Not used for systemic fungal infections </li></ul><ul><li>Used topically for Aspergillus, Candida, Monilial, Trichomonas vaginalis infections </li></ul><ul><li>Natamycin: </li></ul><ul><li>Broad spectrum </li></ul><ul><li>Used topically for – Keratitis, Monilial infections, Trichomonas vaginalis </li></ul>
    19. 19. Imidazoles and Triazoles <ul><li>Azole antifungals </li></ul><ul><li>Imidazoles: </li></ul><ul><ul><li>Topical: Clotrimazole, econazole, miconazole </li></ul></ul><ul><ul><li>Systemic: Ketoconazole </li></ul></ul><ul><li>Triazoles: Fluconazole, itraconazole and voriconazole </li></ul><ul><li>Remember that among imidazoles, only ketocanazole is systemic, other 3 are topical only </li></ul><ul><li>While, Triazoles are used systemically and largely replacing ketoconazole </li></ul>
    20. 20. Azole Structures Fluconazole Ketoconazole
    21. 21. Azoles – Common Mechanism <ul><li>In fungi, the cytochrome P450-enzyme lanosterol 14-alpha demethylase is responsible for the conversion of lanosterol to ergosterol </li></ul><ul><li>Azoles bind to lanosterol 14 α -demethylase inhibiting the production of ergosterol </li></ul><ul><ul><li>Some cross-reactivity is seen with mammalian cytochrome p450 enzymes leading to </li></ul></ul><ul><ul><ul><li>Drug Interactions </li></ul></ul></ul><ul><ul><ul><li>Impairment of steroidneogenesis (ketoconazole, itraconazole) </li></ul></ul></ul>
    22. 22. Individual Agents <ul><li>Ketoconazole: </li></ul><ul><li>Spectrum: yeasts and moulds - poor absorption limits its role for severe infections, generally used in mucosal infections only (dematophytosis) </li></ul><ul><li>Pharmacokinetics </li></ul><ul><ul><li>Variable oral absorption, dependent on pH (often given with cola or fruit juice) </li></ul></ul><ul><ul><li>T1/2 = 7-10 hours </li></ul></ul><ul><ul><li>Protein binding > 99% </li></ul></ul><ul><ul><li>Hepatic, bile and kidney elimination </li></ul></ul>
    23. 23. Ketoconazole – contd. <ul><li>Adverse effects </li></ul><ul><ul><li>N&V, worse with higher doses (800 mg/day) </li></ul></ul><ul><ul><li>Hepatoxicity (2-8%), increase in transaminases, hepatitis </li></ul></ul><ul><ul><li>Dose related inhibition of CYP P450 responsible for testosterone synthesis </li></ul></ul><ul><ul><ul><li>Gynecomastia, oligosperma, decreased libido </li></ul></ul></ul><ul><ul><li>Dose-related inhibition of CYP P450 responsible for adrenal cortisol synthesis </li></ul></ul>
    24. 24. Ketoconazole – contd. <ul><li>Drug Interaction: </li></ul><ul><li>Potent inhibitor of cytochrome P450 3A4 </li></ul><ul><ul><li>Rifampin and phenytoin decrease ketoconazole levels </li></ul></ul><ul><ul><li>Ketoconazole increases cyclosporin, wa r farin, astemizole, corticosteroid, and theophylline levels </li></ul></ul><ul><ul><ul><ul><li>Many of these drug interactions are severe </li></ul></ul></ul></ul><ul><li>Drugs that increase gastric pH will decrease blood levels of ketoconazole </li></ul><ul><ul><li>Antacids, omeprazole, H2 blockers </li></ul></ul><ul><li>Doses: </li></ul><ul><ul><li>Serious infections 800 mg/day PO </li></ul></ul><ul><ul><li>Other: 200-400 mg/day PO </li></ul></ul>
    25. 26. Fluconazole <ul><li>Water soluble having wider range of activity than Ketoconazole </li></ul><ul><li>Good activity against C. albicans and Cryptococcus neoformans </li></ul><ul><li>Non-albicans Candida species more likely to exhibit primary resistance </li></ul>Always resistant Sometimes resistant C. krusei > C. glabrata > C. parapsilosis C. tropicalis C. kefyr
    26. 27. Resistance <ul><li>Primary resistance (seen in severely ill or immunocompromised patients) </li></ul><ul><ul><li>Selection of resistant species or subpopulations </li></ul></ul><ul><ul><li>Replacement with more resistant strain </li></ul></ul><ul><li>Secondary resistance (seen in patients with AIDS who experienced recurrent orophayrngeal candidiasis and received long-term fluconazole therapy) </li></ul><ul><ul><li>Genetic mutation </li></ul></ul><ul><ul><li>Upregulation of efflux pumps </li></ul></ul>
    27. 28. Mechanisms of antifungal resistance <ul><li>Target enzyme modification </li></ul><ul><li>Ergosterol biosynthetic pathway </li></ul><ul><li>Efflux pumps </li></ul><ul><li>Drug import </li></ul>
    28. 29. Fluconazole - Kinetics <ul><li>Available as both IV and PO </li></ul><ul><ul><li>Bioavailibility > 90% </li></ul></ul><ul><li>Pharmacokinetics </li></ul><ul><ul><li>t 1/2 = ~24 hours </li></ul></ul><ul><ul><li>Protein binding < 12% </li></ul></ul><ul><ul><li>Vd 0.85 L/kg (widely distributed) </li></ul></ul><ul><ul><li>>90% excreted unchanged through the kidney </li></ul></ul><ul><li>Dosing </li></ul><ul><ul><li>Mucosal candidiasis </li></ul></ul><ul><ul><ul><li>100-200 mg/day (150 mg tablet vulvovaginal candidiasis) </li></ul></ul></ul><ul><ul><li>Systemic fungal infections </li></ul></ul><ul><ul><ul><li>400-800 mg q24h </li></ul></ul></ul><ul><ul><ul><li>> 800 mg q24h in unstable patient, S-DD isolate, or if non- albicans spp. (except C. krusei ) </li></ul></ul></ul><ul><ul><li>Maintenance for cryptococcal meningitis </li></ul></ul><ul><ul><ul><li>400 mg q24h </li></ul></ul></ul>
    29. 30. Fluconazole - ADRs <ul><li>N&V, rash: </li></ul><ul><ul><li>More likely with high doses and in AIDS patients </li></ul></ul><ul><ul><li>Asymptomatic increase in LFTs (7%) </li></ul></ul><ul><li>Drug interactions: </li></ul><ul><ul><li>May increase phenytoin, cyclosporin, rifabutin, warfarin, and zidovudine concentrations </li></ul></ul><ul><ul><li>Rifampin reduced fluconazole levels to half </li></ul></ul><ul><ul><li>(even though FLU is not a major substrate) </li></ul></ul>
    30. 31. Itraconazole <ul><li>Some Features: </li></ul><ul><li>Newer orally active triazole </li></ul><ul><li>Broader spectrun than KTZ and FCZ – includes moulds like aspergillus </li></ul><ul><li>Fungistatic action but very effective in immunocompromizrd patients </li></ul><ul><li>Steroid hormone synthesis inhibition is absent and no serious hepatotoxicity </li></ul>
    31. 32. Ketoconazole Fluconazole Itraconazole 1 Broad spectrum Still wider range Fungi static 2 Dermatophyte & deep mycosis Cryptococcal & coccidial meningitis immunocompromised patients 3 Absorbed at low pH Good oral absorption Varies with food & pH 4 Highly bound to PP Not much Highly bound 5 More S/E, headache, androgen inhibition Less S/E, headache & rash Hypokalemia, pruritis & dizziness 6 Causes hepatic impairment Mild Not hepatotoxic 7 Inhibit cytochrome P450 Inhibit only fungal P450 No effect 8 Used for Monilial vaginitis. Cushing’s syn Candidiasis, Keratitis, Cryptococcal meningitis Mycosis, meningitis Chromo & paracocci
    32. 33. Local azoles <ul><li>Very popular local azoles are – Clotrimazole, Econazole and Miconazole </li></ul><ul><li>(For Tinea, Ring worm, Athlete’s foot, otomycosis, oral, cutaneous & vaginal candidiasis) </li></ul><ul><li>Mechanism of action is same as that of Ketoconazole i.e. ergosterol inhibition by inhibiting CYP450 </li></ul><ul><li>Clotrimazole is favoured in vaginitis because of long lasting residual effect and once daily dosing </li></ul><ul><li>Miconazole causes frequently vaginal irritation & pelvic cramp. </li></ul><ul><li>Available s lotion, cream, powder, vaginal tablet etc. </li></ul>
    33. 34. Heterocyclic Nitrofurans - Griseofulvin <ul><li>Used for superficial fungal infections by dermatophytes </li></ul><ul><li>Derived from Penicillium griseofulvum but no antibacterial activity </li></ul><ul><li>Effective against most dermatophytes, but not against candida causing deep mycosis </li></ul><ul><li>Dermatophytes actively concentrate it – accounts for selective toxicity against them </li></ul><ul><li>Taken up by newly formed keratin </li></ul>
    34. 35. Griseofulvin - MOA <ul><li>Interferes with mitosis – results in multinucleated and stunted hyphae </li></ul><ul><li>( In most fungi, hyphae are the main mode of vegetative growth, and are collectively called a mycelium yeasts are unicellular fungi that do not grow as hyphae) </li></ul><ul><li>Abnormal metaphase configurations leading to failure of daughter nuclei to fall apart </li></ul><ul><li>(Colchicine and vinca alkloids also mitotic inhibitors but they cause arrest of mitosis) </li></ul><ul><li>Disorientation of polymerized microtubules </li></ul>
    35. 36. Griseofulvin – contd. <ul><li>Pharmacokinetics: </li></ul><ul><li>Given orally and fats improve absorption </li></ul><ul><li>Absorption depends on the particle size </li></ul><ul><li>Duration of treatment depends upon tissue turn over </li></ul><ul><li>1. 3-6 wks for skin & hair </li></ul><ul><li>2. 3-6 months for nails </li></ul><ul><li>Treatment should continue till whole infected tissue is shed off. </li></ul><ul><li>Doses: Used orally only for dermatophytosis (125 to 250 mg 4 times daily, but depends on site of infection </li></ul>
    36. 37. Griseofulvin - ADRs <ul><li>Safe with mild side effects </li></ul><ul><li>1. GIT upsets </li></ul><ul><li>2. CNS symptoms </li></ul><ul><li>3. Hepatotoxicity </li></ul><ul><li>4. Leucopenia </li></ul><ul><li>5. Photosensitivity </li></ul><ul><li>6. Allergy etc. </li></ul><ul><li>Microsomal enzyme inducer </li></ul><ul><li>Causes decrease in activity of anticoagulants </li></ul><ul><li>Cause intolerance to alcohol </li></ul><ul><li>Phenobarbitone reduces its oral absorption so failure of therapy </li></ul>
    37. 38. Flucytosin <ul><li>Fluorinated pyrimidine related to flurouracil </li></ul><ul><li>Restricted spectrum of activity. </li></ul><ul><li>Acquired Resistance due to > result of monotherapy </li></ul><ul><li>Due to: </li></ul><ul><li>1) Decreased uptake (permease activity) </li></ul><ul><li>2) Altered 5-FC metabolism (cytosine deaminase or UMP pyrophosphorylase activity) </li></ul><ul><li>Kinetics: </li></ul><ul><li>Orally absorbed </li></ul><ul><li>Widely distributed even in CSF </li></ul><ul><li>Exc. in urine. </li></ul><ul><li>Converted in fungal cell to 5-FU which is antimetabolite. </li></ul><ul><li>Mammalian cells remain unaffected except few bone marrow cells </li></ul>
    38. 39. Flucytosin <ul><li>Monotherapy : Never </li></ul><ul><li>Candidiasis </li></ul><ul><li>Cryptococcosis </li></ul><ul><li>Aspergillosis </li></ul>} In combination with amphotericin B or fluconazole. <ul><li>Doses: </li></ul><ul><li>Vaginal candidiasis: 200 mg OD for 3 days </li></ul><ul><li>Dermatophytosis; 100-200 mg OD for 7-15 days </li></ul><ul><li>Onychomycosis: 200 mg per day for 3 months </li></ul>ADRs: 1.Mild BM depression 2. Loss of hair 3. Dose should be decreased in the presence of renal impairment
    39. 40. Terbinafine <ul><li>Belongs to a newer allylamine class of antifungals </li></ul><ul><li>Given both orally & locally </li></ul><ul><li>Lipophillic so widely distributed </li></ul><ul><li>Fungicidal in contrast to azoles (fungistatic) </li></ul><ul><li>Acts by non-competitive inhibition of “squalene epoxidase” (early step enzyme in ergosterol synthesis (Image in Slide No. 22) – accumulation of squalene in fungal cells – cidal effect </li></ul><ul><li>Used for dermatophytes & candida </li></ul><ul><li>Dose is 250mg OD for </li></ul><ul><li>2-6 wks </li></ul><ul><li>Locally 1% ointment. </li></ul>
    40. 41. Terbinafine – contd. <ul><li>ADRs </li></ul><ul><li>With oral </li></ul><ul><ul><li>GIT upset </li></ul></ul><ul><ul><li>Hepatic dysfunction </li></ul></ul><ul><ul><li>Rash </li></ul></ul><ul><ul><li>Taste disturbance </li></ul></ul><ul><ul><li>No interaction with CYP450 </li></ul></ul><ul><li>Preparations and doses: </li></ul><ul><ul><li>1% cream 125/250 mg tablets etc. </li></ul></ul><ul><ul><li>Tinea pedis: 250 mg OD for 2-6 weeks </li></ul></ul><ul><ul><li>Onychmycosis: 3-12 months (alternative to fluconazole) </li></ul></ul><ul><li>On local application - d ryness, Erythema , Rash, itching etc. </li></ul>
    41. 42. Thank you

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