Antifungals - drdhriti

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  • There are key differences between mammalian and fungal eukaryotic cells. This is the basis of drug selectivity.
  • 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.
  • 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.
  • 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.
  • This electron micrograph shows the fungistatic effect of the azoles. There is reduced budding from the parent cells.
    This electron micrograph shows the fungistatic effect of the azoles. There is reduced budding from the parent cells.
    This electron micrograph shows the fungistatic effect of the azoles. There is reduced budding from the parent cells
  • 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.
  • Antifungals - drdhriti

    1. 1. Dr. D. K. BrahmaDr. D. K. Brahma Department of PharmacologyDepartment of Pharmacology NEIGRIHMS, ShillongNEIGRIHMS, Shillong Antifungal DrugsAntifungal Drugs
    2. 2. Introduction -Introduction - Also called antimycoticAlso called antimycotic drugsdrugs  Used to treat two types of fungal infection:Used to treat two types of fungal infection: – Superficial fungal infections - skin or mucous membraneSuperficial fungal infections - skin or mucous membrane – Systemic fungal infections - lungs or central nervousSystemic fungal infections - lungs or central nervous systemsystem  Fungi causing mycosis live as commensally or are present in the environment.  Earlier superficial infections were uncommon and systemic rather rare.  Recently there is increase in local as well as systemic fungal infections.  Reason for this is opportunistic infections
    3. 3. Opportunistic infectionsOpportunistic infections  Immuno-suppression due to - Cancer chemotherapy - AIDS – Corticosteroid overuse  Indiscriminate use of broad spectrum antibiotics
    4. 4. Fungal infections  Superficial – Skin – Hair – Nails – Mucous membrane  Deep – Tissues (muscle & connective tissue) – Organs Images of some superficial skin infections
    5. 5. Types of fungal infections - MycosesTypes of fungal infections - Mycoses  Superficial mycosesSuperficial mycoses – Affect the skin, hair and nails – ringworm/tinea orAffect the skin, hair and nails – ringworm/tinea or onychomycosisonychomycosis  Subcutaneous mycoses (tropical)Subcutaneous mycoses (tropical) – Affect the muscle and connective tissue immediatelyAffect the muscle and connective tissue immediately below the skinbelow the skin  Systemic (invasive) mycosesSystemic (invasive) mycoses – Involve the internal organsInvolve the internal organs  Allergic mycosesAllergic mycoses – Affect lungs or sinusesAffect lungs or sinuses – Patients may have chronic asthma, cystic fibrosis or sinusitisPatients may have chronic asthma, cystic fibrosis or sinusitis There is some overlap between these groups
    6. 6. MOST COMMON FUNGALMOST COMMON FUNGAL PATHOGENSPATHOGENS  DermatophytesDermatophytes –– Microsporum,Microsporum, Epidermophyton and TrichophytonEpidermophyton and Trichophyton  CandidaCandida –– C.C. albicans, C. glabrata, C.albicans, C. glabrata, C. tropicalistropicalis  AspergillusAspergillus  CryptococcusCryptococcus  RhizopusRhizopus
    7. 7. Causative fungiCausative fungi  Superficial infections by – Dermatophytes (ring worms): athlete`s foot or tinea pedis, jock itch or tinea cruris, tinea capitis etc. – Candida:Candida: oral thrush, vaginitis and diaper candidiasis etc.  Deep infections are – Candidiasis: Chronic mucocutaneous candidiasis, systemic candidiasis etc. – Aspergillosis: broncho-pulmonary aspergillosis – Coccidiomycosis: pulmonary and disseminated (complications – pneumonia) – Histoplasmosis:Histoplasmosis: H. capsulatum (common in HIV)H. capsulatum (common in HIV)
    8. 8. What are the targets for antifungal therapy?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. Cell Membrane Active AntifungalCell Membrane Active Antifungal Cell membrane 1. Polyene antibiotics - Amphotericin B, lipid formulations - Nystatin (topical) 2. Azole antifungals Imidazoles: • Topical: Clotrimazole, econazole, miconazole • Systemic: Ketoconazole Triazoles: Fluconazole, itraconazole and voriconazole
    10. 10. Polyene antibiotics-Polyene antibiotics-Amphotericin BAmphotericin B  Fermentation product ofFermentation product of Streptomyces nodususStreptomyces nodusus  High affinity for ergosterol present in fungal cell membraneHigh affinity for ergosterol present in fungal cell membrane  Hydrophilic polyhydroxyl chain along one side and a lipophilicHydrophilic polyhydroxyl chain along one side and a lipophilic polyene hydrocarbon chain on the otherpolyene hydrocarbon chain on the other  Binds sterols in fungal cell membrane –Binds sterols in fungal cell membrane – – high affinity for ergosterol present in fungal cell membranehigh affinity for ergosterol present in fungal cell membrane – affinity is less for host cell membrane although closely resemblesaffinity is less for host cell membrane although closely resembles  Creates transmembrane channel and electrolyte leakage.Creates transmembrane channel and electrolyte leakage.  Active against most fungi exceptActive against most fungi except Aspergillus terreusAspergillus terreus,, ScedosporiumScedosporium sppspp..  Bacteria lack sterols so insensitive to polyenesBacteria lack sterols so insensitive to polyenes
    11. 11. Antifungal spectrumAntifungal spectrum  Most Toxic antifungalMost Toxic antifungal  Fungicide at high and static at low conc.Fungicide at high and static at low conc.  Effective againstEffective against – Candida albicansCandida albicans – Histoplasma capsulatumHistoplasma capsulatum – CryptococcusCryptococcus
    12. 12. PharmacokineticsPharmacokinetics  Insoluble in waterInsoluble in water  Unstable at 37degreeUnstable at 37degree  Poorly absorbed from GITPoorly absorbed from GIT  Cannot cross BBBCannot cross BBB  Highly bound to plasma proteinsHighly bound to plasma proteins  Takes 2 months for complete clearance of drugTakes 2 months for complete clearance of drug  Given as I/V infusionGiven as I/V infusion  For fungal meningitis given intrathecallyFor fungal meningitis given intrathecally  Has immuno-stimulant action alsoHas immuno-stimulant action also  Given in immuno-compromised patients for fungalGiven in immuno-compromised patients for fungal infectionsinfections
    13. 13. UsesUses  Broad spectrum antifungalBroad spectrum antifungal  Useful forUseful for 1. Candida that causes1. Candida that causes – oraloral – vaginalvaginal – cutaneous candidiasiscutaneous candidiasis 2. Cryptococcus2. Cryptococcus 3. Histoplasma3. Histoplasma 4. Aspergillosis4. Aspergillosis 5. Also effective for Leishmaniasis(Reserve drug for resistant5. Also effective for Leishmaniasis(Reserve drug for resistant cases of Kala Azar)cases of Kala Azar)
    14. 14. ADRsADRs 1.1. Acute reactions -Acute reactions - occurs with each infusionoccurs with each infusion – Chills, Nausea, Vomiting, Pain, Fever, Aches, DyspnoeaChills, Nausea, Vomiting, Pain, Fever, Aches, Dyspnoea – So corticosteroids are administered along with the drugSo corticosteroids are administered along with the drug 1.1. ThrombophlebitisThrombophlebitis 2.2. Bone marrow depressionBone marrow depression - Reversible anemia- Reversible anemia 3.3. On intrathecal injectionOn intrathecal injection – Headache, Vomiting,– Headache, Vomiting, Nerve paralysisNerve paralysis 4.4. Renal toxicity leading toRenal toxicity leading to – Azotemia, Decreased– Azotemia, Decreased GFR, Acidosis, Hypokalemia, Inability to conc.GFR, Acidosis, Hypokalemia, Inability to conc. urineurine
    15. 15. Newer Amphotericin BNewer Amphotericin B They are developed to overcomeThey are developed to overcome 1. Side effects1. Side effects 2. To improve tolerability2. To improve tolerability 3. To get the drug at site of action3. To get the drug at site of action 4. To reduce the toxicity i.e.. Less nephrotoxic and minimal4. To reduce the toxicity i.e.. Less nephrotoxic and minimal anemiaanemia Formulations are:Formulations are: 1. Amphotericin B lipid complex1. Amphotericin B lipid complex 2. Amphotericin B colloidal dispersion2. Amphotericin B colloidal dispersion 3. Liposomal Amphotericin B3. Liposomal Amphotericin B (Only drawback of these formulations is less efficacy)(Only drawback of these formulations is less efficacy)
    16. 16. Drug Interactions of Amphotericin BDrug Interactions of Amphotericin B  With Flucytocin-synergistic actionWith Flucytocin-synergistic action  Rifampicin and Minocyclin –Rifampicin and Minocyclin – – Both potentiate Amphotericin BBoth potentiate Amphotericin B  Vancomycin and Aminoglycoside –Vancomycin and Aminoglycoside – – Both increase risk of nephrotoxicityBoth increase risk of nephrotoxicity  Preparation and doses:Preparation and doses: – 50 – 100 mg four times a day orally50 – 100 mg four times a day orally – 3% ear drops3% ear drops – Systemic: 50 mg vial (one vial diluted in 500 ml of 5%Systemic: 50 mg vial (one vial diluted in 500 ml of 5% glucose and initially 1 mg test dose followed by infusionglucose and initially 1 mg test dose followed by infusion for 4 – 8 Hrs)for 4 – 8 Hrs)
    17. 17. NystatinNystatin  Similar to Amphotericin B but moreSimilar to Amphotericin B but more toxictoxic thanthan Amphotericin BAmphotericin B  Used only for superficial candidiasis ofUsed only for superficial candidiasis of Skin, Mouth, Vagina, IntestineSkin, Mouth, Vagina, Intestine  As ointment ,oral tablets & suppositoriesAs ointment ,oral tablets & suppositories  Available as tablets and ointments (1 to 5 lacs U)Available as tablets and ointments (1 to 5 lacs U) – also vaginal tablets– also vaginal tablets  Orally not absorbed but can be used in monilialOrally not absorbed but can be used in monilial diarrhoeadiarrhoea
    18. 18. Other PolyenesOther Polyenes 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
    19. 19. Imidazoles and TriazolesImidazoles and Triazoles Azole antifungals  Imidazoles: – Topical: Clotrimazole, econazole, miconazole – Systemic: Ketoconazole  Triazoles: Fluconazole, itraconazole and voriconazole  Remember that among imidazoles, onlyRemember that among imidazoles, only ketocanazole is systemic, other 3 are topical onlyketocanazole is systemic, other 3 are topical only  While, Triazoles are used systemically and largelyWhile, Triazoles are used systemically and largely replacing ketoconazolereplacing ketoconazole
    20. 20. Azole StructuresAzole Structures Fluconazole Ketoconazole
    21. 21. AzolesAzoles – Common Mechanism– Common Mechanism • In fungi, the cytochrome P450- enzyme lanosterol 14-alpha demethylase is responsible for the conversion of lanosterol to ergosterol • Azoles bind to lanosterol 14α- demethylase inhibiting the production of ergosterol – Some cross-reactivity is seen with mammalian cytochrome p450 enzymes leading to • Drug Interactions • Impairment of steroidneogenesis (ketoconazole, itraconazole)
    22. 22. Effect of azoles on C. albicansEffect of azoles on C. albicans Before exposure After exposure Decreased budding from the parent cells
    23. 23. Individual AgentsIndividual Agents Ketoconazole:Ketoconazole:  Spectrum: yeasts and moulds - poor absorptionSpectrum: yeasts and moulds - poor absorption limits its role for severe infections, generally usedlimits its role for severe infections, generally used in mucosal infections only (dematophytosis)in mucosal infections only (dematophytosis)  PharmacokineticsPharmacokinetics – Variable oral absorption, dependent on pH (often givenVariable oral absorption, dependent on pH (often given with cola or fruit juice)with cola or fruit juice) – T1/2 = 7-10 hoursT1/2 = 7-10 hours – Protein binding > 99%Protein binding > 99% – Hepatic, bile and kidney eliminationHepatic, bile and kidney elimination
    24. 24. Ketoconazole – contd.Ketoconazole – contd.  Adverse effectsAdverse effects – N&V, worse with higher doses (800 mg/day)N&V, worse with higher doses (800 mg/day) – Hepatoxicity (2-8%), increase in transaminases,Hepatoxicity (2-8%), increase in transaminases, hepatitishepatitis – Dose related inhibition of CYP P450 responsibleDose related inhibition of CYP P450 responsible for testosterone synthesisfor testosterone synthesis  Gynecomastia, oligosperma, decreased libidoGynecomastia, oligosperma, decreased libido – Dose-related inhibition of CYP P450Dose-related inhibition of CYP P450 responsible for adrenal cortisol synthesisresponsible for adrenal cortisol synthesis
    25. 25. Ketoconazole – contd.Ketoconazole – contd. Drug Interaction:Drug Interaction:  Potent inhibitor of cytochrome P450 3A4Potent inhibitor of cytochrome P450 3A4 – Rifampin and phenytoin decrease ketoconazole levelsRifampin and phenytoin decrease ketoconazole levels – Ketoconazole increases cyclosporin, waKetoconazole increases cyclosporin, warrfarin, astemizole,farin, astemizole, corticosteroid, and theophylline levelscorticosteroid, and theophylline levels – Many of these drug interactions are severeMany of these drug interactions are severe  Drugs that increase gastric pH will decrease blood levels ofDrugs that increase gastric pH will decrease blood levels of ketoconazoleketoconazole – Antacids, omeprazole, H2 blockersAntacids, omeprazole, H2 blockers  Doses:Doses: – Serious infections 800 mg/day POSerious infections 800 mg/day PO – Other: 200-400 mg/day POOther: 200-400 mg/day PO
    26. 26. FluconazoleFluconazole  Water soluble having wider range of activity thanWater soluble having wider range of activity than KetoconazoleKetoconazole  Good activity against C. albicans and CryptococcusGood activity against C. albicans and Cryptococcus neoformansneoformans  Non-albicans Candida species more likely to exhibitNon-albicans Candida species more likely to exhibit primary resistanceprimary resistance Always resistant Sometimes resistant C. krusei > C. glabrata > C. parapsilosis C. tropicalis C. kefyr
    27. 27. ResistanceResistance  Primary resistancePrimary resistance (seen in severely ill or(seen in severely ill or immunocompromised patients)immunocompromised patients) – Selection of resistant species or subpopulationsSelection of resistant species or subpopulations – Replacement with more resistant strainReplacement with more resistant strain  Secondary resistanceSecondary resistance (seen in patients with(seen in patients with AIDS who experienced recurrent orophayrngealAIDS who experienced recurrent orophayrngeal candidiasis and received long-term fluconazolecandidiasis and received long-term fluconazole therapy)therapy) – Genetic mutationGenetic mutation – Upregulation of efflux pumpsUpregulation of efflux pumps
    28. 28. Mechanisms of antifungal resistanceMechanisms of antifungal resistance  Target enzymeTarget enzyme modificationmodification  ErgosterolErgosterol biosyntheticbiosynthetic pathwaypathway  Efflux pumpsEfflux pumps  Drug importDrug import
    29. 29. Fluconazole - KineticsFluconazole - Kinetics  Available as both IV and POAvailable as both IV and PO – Bioavailibility > 90%Bioavailibility > 90%  PharmacokineticsPharmacokinetics – t 1/2 = ~24 hourst 1/2 = ~24 hours – Protein binding < 12%Protein binding < 12% – Vd 0.85 L/kg (widely distributed)Vd 0.85 L/kg (widely distributed) – >90% excreted unchanged through the kidney>90% excreted unchanged through the kidney  DosingDosing 1.1. Mucosal candidiasisMucosal candidiasis  100-200 mg/day (150 mg tablet vulvovaginal candidiasis)100-200 mg/day (150 mg tablet vulvovaginal candidiasis) 1.1. Systemic fungal infectionsSystemic fungal infections  400-800 mg q24h400-800 mg q24h  >> 800 mg q24h in unstable patient, S-DD isolate, or if non-800 mg q24h in unstable patient, S-DD isolate, or if non-albicansalbicans spp.spp. (except(except C. kruseiC. krusei)) 1.1. Maintenance for cryptococcal meningitisMaintenance for cryptococcal meningitis  400 mg q24h400 mg q24h
    30. 30. Fluconazole - ADRsFluconazole - ADRs  N&V, rash:N&V, rash: – More likely with high doses and in AIDS patientsMore likely with high doses and in AIDS patients – Asymptomatic increase in LFTs (7%)Asymptomatic increase in LFTs (7%)  Drug interactions:Drug interactions: – May increase phenytoin, cyclosporin, rifabutin,May increase phenytoin, cyclosporin, rifabutin, warfarin, and zidovudine concentrationswarfarin, and zidovudine concentrations – Rifampin reduced fluconazole levels to halfRifampin reduced fluconazole levels to half (even though FLU is not a major substrate)(even though FLU is not a major substrate)
    31. 31. ItraconazoleItraconazole Some Features:Some Features:  Newer orally active triazoleNewer orally active triazole  Broader spectrun than KTZ and FCZ –Broader spectrun than KTZ and FCZ – includes moulds like aspergillusincludes moulds like aspergillus  Fungistatic action but very effective inFungistatic action but very effective in immunocompromizrd patientsimmunocompromizrd patients  Steroid hormone synthesis inhibition isSteroid hormone synthesis inhibition is absent and no serious hepatotoxicityabsent and no serious hepatotoxicity
    32. 32. KetoconazoleKetoconazole FluconazoleFluconazole ItraconazoleItraconazole 11 Broad spectrumBroad spectrum Still wider rangeStill wider range Fungi staticFungi static 22 DermatophyteDermatophyte & deep mycosis& deep mycosis Cryptococcal & coccidialCryptococcal & coccidial meningitismeningitis immunocompromisedimmunocompromised patientspatients 33 Absorbed at low pHAbsorbed at low pH Good oral absorptionGood oral absorption Varies with food & pHVaries with food & pH 44 Highly bound to PPHighly bound to PP Not muchNot much Highly boundHighly bound 55 More S/E, headache, androgenMore S/E, headache, androgen inhibitioninhibition Less S/E, headache & rashLess S/E, headache & rash Hypokalemia, pruritis &Hypokalemia, pruritis & dizzinessdizziness 66 Causes hepatic impairmentCauses hepatic impairment MildMild Not hepatotoxicNot hepatotoxic 77 Inhibit cytochrome P450Inhibit cytochrome P450 Inhibit only fungal P450Inhibit only fungal P450 No effectNo effect 88 Used for Monilial vaginitis.Used for Monilial vaginitis. Cushing’s synCushing’s syn Candidiasis, Keratitis,Candidiasis, Keratitis, Cryptococcal meningitisCryptococcal meningitis Mycosis, meningitisMycosis, meningitis Chromo & paracocciChromo & paracocci
    33. 33. Local azolesLocal azoles  Very popular local azoles are – Clotrimazole, Econazole and Miconazole  (For Tinea, Ring worm, Athlete’s 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 s lotion, cream, powder, vaginal tablet etc.Available s lotion, cream, powder, vaginal tablet etc.
    34. 34. Heterocyclic Nitrofurans -Heterocyclic Nitrofurans - GriseofulvinGriseofulvin  Used for superficial fungal infections byUsed for superficial fungal infections by dermatophytesdermatophytes  Derived from Penicillium griseofulvum butDerived from Penicillium griseofulvum but no antibacterial activityno antibacterial activity  Effective against most dermatophytes, butEffective against most dermatophytes, but not against candida causing deep mycosisnot against candida causing deep mycosis  Dermatophytes actively concentrate it –Dermatophytes actively concentrate it – accounts for selective toxicity against themaccounts for selective toxicity against them  Taken up by newly formed keratinTaken up by newly formed keratin
    35. 35. Griseofulvin - MOAGriseofulvin - MOA  Interferes with mitosis – results inInterferes with mitosis – results in multinucleated and stuntedmultinucleated and stunted hyphaehyphae ((In most fungi, hyphae are the main mode of vegetative growth, and areIn most fungi, hyphae are the main mode of vegetative growth, and are collectively called a mycelium yeasts are unicellular fungi that do notcollectively called a mycelium yeasts are unicellular fungi that do not grow as hyphae)grow as hyphae)  Abnormal metaphase configurations leadingAbnormal metaphase configurations leading to failure of daughter nuclei to fall apartto failure of daughter nuclei to fall apart (Colchicine and vinca alkloids also mitotic inhibitors but they cause(Colchicine and vinca alkloids also mitotic inhibitors but they cause arrestarrest of mitosis)of mitosis)  Disorientation of polymerized microtubulesDisorientation of polymerized microtubules
    36. 36. Griseofulvin – contd.Griseofulvin – contd. Pharmacokinetics:Pharmacokinetics:  Given orally and fats improve absorptionGiven orally and fats improve absorption  Absorption depends on the particle sizeAbsorption depends on the particle size  Duration of treatment depends upon tissue turn overDuration of treatment depends upon tissue turn over 1. 3-6 wks for skin & hair1. 3-6 wks for skin & hair 2. 3-6 months for nails2. 3-6 months for nails  Treatment should continue till whole infected tissue is shedTreatment should continue till whole infected tissue is shed off.off. Doses:Doses: Used orally only for dermatophytosis (125 to 250 mgUsed orally only for dermatophytosis (125 to 250 mg 4 times daily, but depends on site of infection4 times daily, but depends on site of infection
    37. 37. Griseofulvin - ADRsGriseofulvin - ADRs  Safe with mild side effectsSafe with mild side effects 1. GIT upsets1. GIT upsets 2. CNS symptoms2. CNS symptoms 3. Hepatotoxicity3. Hepatotoxicity 4. Leucopenia4. Leucopenia 5. Photosensitivity5. Photosensitivity 6. Allergy etc.6. Allergy etc.  Microsomal enzyme inducerMicrosomal enzyme inducer  Causes decrease in activity of anticoagulantsCauses decrease in activity of anticoagulants  Cause intolerance to alcoholCause intolerance to alcohol  Phenobarbitone reduces its oral absorption so failure ofPhenobarbitone reduces its oral absorption so failure of therapytherapy
    38. 38. FlucytosinFlucytosin  Fluorinated pyrimidine related to flurouracilFluorinated pyrimidine related to flurouracil  Restricted spectrum of activity.Restricted spectrum of activity.  Acquired Resistance due to > result of monotherapyAcquired Resistance due to > result of monotherapy  Due to:Due to: 1) Decreased uptake (permease activity)1) Decreased uptake (permease activity) 2) Altered 5-FC metabolism (cytosine deaminase or UMP2) Altered 5-FC metabolism (cytosine deaminase or UMP pyrophosphorylase activity)pyrophosphorylase activity) Kinetics:Kinetics:  Orally absorbedOrally absorbed  Widely distributed even in CSFWidely distributed even in CSF  Exc. in urine.Exc. in urine.  Converted in fungal cell to 5-FU which is antimetabolite.Converted in fungal cell to 5-FU which is antimetabolite.  Mammalian cells remain unaffected except few bone marrow cellsMammalian cells remain unaffected except few bone marrow cells
    39. 39. FlucytosinFlucytosin Monotherapy : NeverMonotherapy : Never  CandidiasisCandidiasis  CryptococcosisCryptococcosis  ?Aspergillosis?Aspergillosis } In combination with amphotericin B or fluconazole. Doses: 1. Vaginal candidiasis: 200 mg OD for 3 days 2. Dermatophytosis; 100-200 mg OD for 7-15 days 3. Onychomycosis: 200 mg per day for 3 months ADRs: 1.Mild BM depression 2. Loss of hair 3. Dose should be decreased in the presence of renal impairment
    40. 40. TerbinafineTerbinafine  Belongs to a newer allylamine class of antifungalsBelongs to a newer allylamine class of antifungals  Given both orally & locallyGiven both orally & locally  Lipophillic so widely distributedLipophillic so widely distributed  Fungicidal in contrast to azoles (fungistatic)Fungicidal in contrast to azoles (fungistatic)  Acts by non-competitive inhibition ofActs by non-competitive inhibition of “squalene epoxidase”“squalene epoxidase” (early step enzyme in ergosterol synthesis (Image in Slide(early step enzyme in ergosterol synthesis (Image in Slide No. 22) – accumulation of squalene in fungal cells – cidalNo. 22) – accumulation of squalene in fungal cells – cidal effecteffect  Used for dermatophytes & candidaUsed for dermatophytes & candida  Dose is 250mg OD for 2-6 wksDose is 250mg OD for 2-6 wks  Locally 1% ointmentLocally 1% ointment.
    41. 41. Terbinafine – contd.Terbinafine – contd. ADRsADRs  With oralWith oral – GIT upsetGIT upset – Hepatic dysfunctionHepatic dysfunction – RashRash – Taste disturbanceTaste disturbance – No interaction with CYP450No interaction with CYP450  Preparations and doses:Preparations and doses: – 1% cream 125/250 mg tablets etc.1% cream 125/250 mg tablets etc. – Tinea pedis: 250 mg OD for 2-6 weeksTinea pedis: 250 mg OD for 2-6 weeks – Onychmycosis: 3-12 months (alternative to fluconazole)Onychmycosis: 3-12 months (alternative to fluconazole) • On local application -On local application - ddryness, Erythemaryness, Erythema,, Rash,Rash, itching etc.itching etc.
    42. 42. Expected QuestionsExpected Questions  Classify antifungals. Write MOA, ADRs and Uses of Amphotericin BClassify antifungals. Write MOA, ADRs and Uses of Amphotericin B  Classify azoles. Write briefly on MOA and Uses of azolesClassify azoles. Write briefly on MOA and Uses of azoles  Write briefly on MOA and mechanism of resistance of azolesWrite briefly on MOA and mechanism of resistance of azoles  MCQs:MCQs: 1.1. Amphotericin B is: fungistatic, fungicidal etc. and other choicesAmphotericin B is: fungistatic, fungicidal etc. and other choices 2.2. Azoles: inhibits ergosterol, inhibits nucleic acid, inhibits microtubule etc.Azoles: inhibits ergosterol, inhibits nucleic acid, inhibits microtubule etc. 3.3. Ketoconazole may cause: cortisol deficiency, testosterone deficiency etc.Ketoconazole may cause: cortisol deficiency, testosterone deficiency etc. 4.4. Griseofulvin causes: destruction of fungal microtubule, inhibits fungal cellGriseofulvin causes: destruction of fungal microtubule, inhibits fungal cell membrane etc.membrane etc. 5.5. Griseofuvin is best administered: with fatty diet, in empty stomach etc.Griseofuvin is best administered: with fatty diet, in empty stomach etc.  Short Notes:Short Notes: – Fluconazole, Griseofulvin, Ketoconazole, Clotrimazole, TerbinafineFluconazole, Griseofulvin, Ketoconazole, Clotrimazole, Terbinafine
    43. 43. Thank youThank you

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