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PH3502-Chemotherapy and selective toxcitiy > lec 5- Anti-fungal agents > Flashcards

lec 5- Anti-fungal agents Flashcards

1
Q

Infections caused by yeast

A
  • Candida albicans causes infections of mucous membranes (thrush) and blood stream
  • Cryptococcus Neoformans causes pneumonia and meningitis
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2
Q

Infections caused by moulds

A
  • Filamentous fungi (dermatophytes)
  • Trichophyton rubrum
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3
Q

Human ringworm

A
  • Tinea corporis
  • Classic circular ringworm inflammatory lesion- spreading outwards/healing in the centre
  • Trichophyton sp.
  • Athletes foot (Tinea pedis)
  • Broken skin and inflammation lesions between toes
  • Topical: Azole or Terbinafine
  • Allylamine= C=C bond with CH2 then amine
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4
Q

Targets for Antifungal drug development

A
  • Mannoproteins
  • Caspofungin
  • b-(1,6)-glucan
  • b-(1,3)-glucan
  • Chitin
  • Phospholipid bilayer- Ergosterol- polyenes
  • DNA/RNA synthesis- 5-FC
  • Ergosterol synthesis pathway- imidazoles, triazoles
  • Squalene- terbinafine
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5
Q

Ergosterol/Cholesterol antifungal drugs

A
  • Work by exploiting differences between mammalian and fungal cells to kill the fungal organism without dangerous effects on the host
  • Both fungi and humans eukaryotes
  • Difficult to find or design drugs that target fungi without affecting human cells (side effects)
  • Fungal cell membranes have unique sterol (ergo)- which replaces cholesterol in the mammalian cell membrane
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6
Q

Sterol chemical structures

A
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7
Q

Cholesterol/Ergosterol- Similarities and Differences

A

Similarities

  • Ring A/B/C/D tetracyclic
  • Template and side chain
  • Secondary alcohol

Differences

  • The double bond in ring B (diene)
  • A side chain Me, double bond
  • These Structural differences are key to antifungal chemotherapy
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8
Q

Amphotericin B

A
  • Target = Ergosterol
  • Broad spectrum polyene macrolide antibiotic
  • Large ring cyclic ester
  • Most potent antifungal agent for systemic mycosis, in clinical use since 1960
  • Fungicidal drug at higher concentrations and static at lower levels

Produced by Streptomyses nodosum natural product

  • CSF conc= 2-3% of blood conc
  • Highest concentration in liver, spleen, bone marrow with less in kidneys and lungs
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9
Q

Mechanism of action of polyene antifungal

A
  • Amphotericin B
  • Binds to ergosterol
  • Intercalation of cell membrane (makes pores/holes into the membrane)
  • allows ions (Na, K, Ca) as well as proteins to flow out of the cell
  • low conc = fungistatic
  • High conc= fungicidal
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10
Q

Mechanism of action

A
  • Binds to fungal cell membrane (ergosterol) =>
  • Forms pores =>
  • Alters permeability and transport =>
  • Cell death
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11
Q

Clinical Use

A
  • Treatment of nearly all life threatening mycotic infections
  • For systemic disease: slow IV
  • Local: topical application
  • Cholesterol, present in host cell membranes, closely resembles fungal ergosterol
  • Result: High toxicity of AM-B in humans
  • Highlight- Fungal arthritis = Local injection
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12
Q

Liposomal amphotericin B

A
  • New lipid formulations
  • Amphotericin B is incorporated into lipid formulations to reduce toxicity and enhance efficacy + bioavailability
  • This allows higher dose to be used without increasing the toxicity
  • Much more expensive than ordinary AM-B
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13
Q

Target: Cell wall- antifungal agents

A
  • Cyclic lipo-peptide
  • Caspofungin (Cancidas, Merck): life-threatening systemic mycoses but not cryptococcal meningitis
  • Structure: A semi-synthetic echinocandin Cyclic lipoprotein
  • Mechanism: inhibition of synthesis of 1,3,-b-D-glucan in fungal cell walls
  • Anidulafungin (Ecalta, Pfizer): similar to caspofungin
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14
Q

Caspofungin- structure

A
  • cyclic
  • Amide bonds
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15
Q

Echinocandins

A
  • The newest class of antifungal
  • Active against candida and aspergillus (mould + yeast)

Adverse effects

  • Extremely well tolerated- specific to fungi cell wall
  • Minor GI side effects
  • Flushing
  • Elevated Liver enzymes (Caspofungin + Cyclosporine)
  • Histamine release during IV infusion
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16
Q

Mechanism of action

A
  • Inhibit the synthesis of b-glycan in the fungal cell wall =>
  • Disruption of the fungal cell wall and cell death
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17
Q

Molecular target DNA

A

FLUCYTOSINE 5-FC

  • 5-fluorocytosine
  • pyrimidine
  • Compare 5-FU anticancer agent
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18
Q

Flucytosine (5-FC)

A
  • Pyrimidine Anti-metabolite, narrow-spectrum fungistatic activity
  • Water-soluble- good BBB penetration
  • Oral only
  • poor protein binding
  • CSF conc- 75% serum concentration- Excellent CSF
  • Treatment of fungal meningitis- BBB penetration
19
Q

5-fluorocytosine inhibits DNA synthesis in fungi

A
  • 5-Fluorocytosin =(fungal deaminase)=>
  • 5-Fluorouracil ==>
  • 5F-dUMP => blocks conversion to dTMP by thmidylate synthetase, DNA synthesis inhibited
  • 5-FU = anti-cancer
20
Q

Mode of action

A
  • It is converted only in fungus by fungal deaminase to 5-FU- desamination
  • 5-FU is then converted to 5-fluorodeoxyuridine monophosphate (FdUMP)- glycosylation
  • And then fluorouridine triphosphate (FUTP), phosphorylation/ kinase
  • Which then inhibit DNA and RNA synthesis (enzyme inhibitor)
  • BONUS: Flucytosine is taken up by fungal cells via the enzyme cytosine permease- Selective uptake
    • Not in humans
21
Q

Why doesn’t the drug act on human cells

A
  • Human cells are unable to convert the parent drug to its active metabolites
22
Q

Adverse effects

A
  • Bone marrow toxicity with anemia, leukopenia thrombocytopenia
  • Mammalian bone marrow cell have the capacity to covert 5-FC => 5-FU
  • GI disturbance
  • Mild and reversible liver dysfunction
23
Q

Griseofulvin

A
  • A very insoluble molecule, poor bioavailability of drug (need for new formulations)
  • Fungistatic- derived from a species of Penicillium, isolated natural product
  • Better absorption when given with fatty foods
  • It is deposited in the newly forming skin where it binds to keratin, protecting the skin from new infection
  • Interferes with spindle formation in dividing cells and therefore with mitosis, unique mode of action
  • Spiro compound
  • Chiral
  • natural product- benzofuran
24
Q

Overview: antifungal agents

A
  1. Griseofulvin- oral treatment of dermatophytes
  2. 5-fluorocytosin (5-FC)- life-threatening systemic mycoses (candidiasis, cryptococcal meningitis)
  3. Polyenes (amphotericin, nystatin): Life-threatening systemic mycoses (candidiasis, aspergillosis, cryptococcal meningitis)
  4. Imidazole (miconazole, ketoconazole)
  5. Triazoles (Fluconazole, intraconazole): candidiasis superficial
  6. Candidal infection (thrush): topical mycoses
  7. Allylamines (terbinafine)- dermatophytes (skin, nails)
  8. Echinocandins- newest class, act on cell wall
25
Q

From metronidazole to imidazole lead structure

A
  • Metronidazole active: anaerobic organisms (Trichomonas vaginalis, clostridia, Bacteroides species)
  • Converted to active radical of the nitro group inside the cells which causes DNA strand breakage
26
Q

Azoles- TARGET= Ergosterol synthesis

A
  1. Imidazoles
    • Ketoconazole
    • Miconazole
    • Clotrimazole
  2. Triazoles
    • Intraconazole
    • Fluconazole
    • Voriconazole
    • Posaconazole
27
Q

Triazoles

A
  • High CSF: Serum conc ration is very high for fluconazole meaning it can be used for fungal meningitis
  • Higher half-life means OD administration
    *
28
Q

Differences AZOLES

A
  • BROAD SPECTRUM OF ACTIVITY
  • Differences in water solubility
  • Absorption, membrane penetration
  • Half-life/ elimination
  • ADME not MOA
  • Formulation, route of administration
29
Q

Feature

A
  • Fluconazole
  • High water solubility
  • High membrane penetration
  • Half-life
  • Imidazole, triazole, extra nitrogen atom, N polar
  • Small, low MW
  • F atom in para position blocks metabolism, hydroxylation
30
Q

Adverse effects

A
  • Relatively nontoxic- allow slight toxicity because they are only acute treatment
  • Minor GI upset
  • Abnormalities in liver enzymes- Inhibit cytochrome P450 enzymes
  • Very rarely, clinical hepatitis
31
Q

Mechanism of Action

A
  • Inhibition of fungal cytochrome P450 enzymes ==>
  • Reduction of ergosterol synthesis
32
Q

ChE synthesis

A
  • Lanosterol-Demethylase= P450 enzyme
33
Q

Ergosterol synthesis

A
34
Q

AZOLES

A
  • Inhibition of biosynthesis, ergosterol
    • In humans, lanosterol gets converted into ChE
    • In micro-organism, it gets converted into ergosterol
  • P450, oxidising enzymes, catalyse the oxidation
  • Special case, demethylation, 14-alpha-demethylase
  • Newly formed double bond, in conjugation, to double bond
35
Q

Ketoconazole

A
  • Older Imidazole, more toxic, replaced by itraconazole, but less costly
  • The first oral AZOLE introduced into clinical use
  • It is less selective for fungal P450 than are the newer azoles
  • Absorption variable (better in acidic medium)
  • Penetration in brain & CSF is poor
  • In high doses inhibits adrenocortical steroids and testosterone synthesis, resulting in gynecomastia in some males
36
Q

Itraconazole

A
  • Triazole
  • Broad-spectrum antifungal with fungistatic action
  • MOA: inhibits fungal ergosterol synthesis like other azoles
  • Drug absorption is increased by good and by low gastric pH
  • Pentration of drug in brain& CSF in poor
  • Much more selective than ketoconazole
37
Q

Posaconazole

A
  • The newest triazole
  • It is the broadest spectrum member of the azole family
  • Selectivity: it is the only azole with significant activity against the agents of zygomycosis and mucormycosis
38
Q

Fluconazole

A
  • Broad-spectrum fungicidal drug
  • It is also effective against some Gram-positive & anaerobic bacteria
  • Good oral bioavailability, 94% is absorbed
  • Penetration in brain & CSF is good, hence used for cryptococcal meningitis
    *
39
Q

Topical AZOLES

A
  • Clotrimazole, miconazole
  • Vulvovaginal candidiasis, oral thrush, dermatophyte infections, including tinea corporis, tinea pedis and tinea cruris
  • Absorption is negligible, and adverse effects are rare
  • Topical and shampoo forms of ketoconazole for seborrheic dermatitis and pityriasis Versicolor
40
Q

Topical Allylamines

A
  • Terbinafine & Naftifine
  • Naftifine: Synthetic allylamine
  • Both are effective for treatment of tinea cruris and tinea corporis
  • Terbinafine concentrates in skin and especially at nail beds, making it quite useful for fungal nail infections
  • Inhibition biosynthesis ergosterol
  • MOA: Terbinafine inhibits squalene epoxidase in the early stage of ergosterol synthesis in fungi
  • Accumulation of intracellular squalene (toxic to the organism) & deficient ergosterol synthesis subsequent fungal cell death
  • Keratophillic, fungicidal
  • Dermatophytoses, Human ring worm
41
Q

MOA of allylamines

A
  • Like the azole drugs, allylamines interfere with ergosterol biosynthesis
  • But rather than interacting with the P450 system/ 14-Alpha-demethylase
  • Terbinafine inhibits the fungal enzyme squalene epoxidase (similar structure to squalene)
  • This leads additionally to the accumulation of the sterol Squalene which is toxic to the organism
42
Q

Overview biosynthesis ergosterol

A
43
Q

Targets for antifungal drug development

A

PH3502-Chemotherapy and selective toxcitiy (21 decks)

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