Antifungal Agents Flashcards
Fungi
• Eukaryotic cells with rigid cell walls
• Microscopic, mostly invisible organisms
• Isolated single cells or chains of cells
Fungi
• Usually only observe the ‘fruit’ of the fungus
• The body of the fungus (mycelium) is composed of a branching network of filaments (hyphae)
• Fungi are a valuable source of pharmaceuticals
• Few fungi cause disease
Types of Fungal Infections (Mycoses)
- Superficial mycoses
- Affect the skin, hair and nails
- Subcutaneous mycoses
- Affect the muscle and connective tissue immediately below the skin
• Systemic mycoses
• Involve the internal organs
• Primary versus
opportunistic
- Allergic mycoses
- Affect lungs or sinuses
- Patients may have chronic asthma, sinusitis or cystic fibrosis
Targets for Antifungal Therapy
- echinocandins
- azoles
- terbinafine, naftifine, amorolfine
- griseofuluin
- flucytosine
Key Classes of Antifungals
- Azoles: fluconazole, voriconazole, itraconazole
- Inhibit lanosterol 14-a demethylase, inhibit steroid synthesis pathway
• Polyenes: amphotericin B, nystatin • Bind to ergosterol to form pores
- 5-Flucytosine
- Inhibits DNA and RNA synthesis
- Echinocandins: caspofungin, micafungin (natural products)
- Inhibit (1,3)-D-glucan synthase - inhibit carbaohdrate rich cell wall
- Allylamines: terbinafine, amorolifine
- Inhibit squalene epoxidase within the steroid synthesis pathway
• 5-Flucytosine is also
a useful chemotherapy agent
• Imidazoles vs. triazoles
• Imidazoles: 5 membered rings that contain 2 N’s.
Triazoles: 5 membered rings that contain 3 Ns.
- Synthetic, fungistatic, broad spectrum
- Inhibit lanosterol 14- demethylase
- Inhibit transformation of Candida yeast cells into hyphae
- Depletion of ergosterol limits the binding of amphotericin and other polyenes
Imidiazole Antifungals
- First orally-active azole for treatment of systemic infections but is toxic and relapse is common
- Principal hazard is potentially fatal liver toxicity
- Inhibition of testosterone synthesis → gynaecomastia
- Interactions with cyclosporin, rifampicin, H2 anatagonists
Triazole Antifungals
- Fluconazole is well adsorbed and is orally-active
- Fungicidal concentrations achieved in most tissues • Unwanted effects are much reduced
- Itraconazole is also orally-active
- Rapidly undergoes extensive metabolism
- Highly lipophilic so alternative formulations are important • Side effects can include liver damage
Azoles: Drug Interactions
diagram slide 16
3A4 - ketaconazole, fluconazole, itracooazole, voriconazole
2C19 - keto, fluco, vori 2D6 - keto 2C9 - keto, fluco, vori 1A2 - keto 2E1 - keto 2C8 - keto, vori
Resistance to Azoles
- Well-known particularly for fluconazole
- Data available also for other azoles
- A significant clinical problem
RESISTANCE TO FLUCONAZOLE
PRIMARY
C. krusei Aspergillus
C. glabrata
C. norvegensis…
SECONDARY
C. albicans
C. dubliniensis…
• Single point mutation of ERG11 gene -> Altered lanosterol 14- demethylase
• Overexpression of ERG11 gene
-> Increased production of lanosterol 14- demethylase
• Alterations in ERG3 or ERG5 genes
-> Production of low affinity sterols
• Increase in mRNA levels of CDR1 or MDR1 genes
-> Decreased accumulation of the azole in fungal cell
Polyene Antifungals
- Natural products from Streptomyces spp.
- Act upon the fungal cell membranes
- Bind selectively to ergosterol
- Form transmembrane ion channels
- Selective for fungi over host cells
humans do not have..
humans do not have ergosterol in their cell walls
Amphotericin B key region
slide 22
not absorbed very well due to hydrophobicity - poorly soluble molecule not good when you take it orally
-by forming pores it causes ions to leak out - ions will cross and the cell will die
Amphotericin B
Poorly absorbed when taken orally
• Administered i.v. complexed with lipids/within liposomes
• Highly protein bound
• Excreted slowly; traces can still be found in urine up to two months following treatment
Amphotericin B: Side Effects
- Renal toxicity due to impaired glomerular filtration
- Hypokalaemia, hypomagnesaemia, anaemia
- Injection frequently results in chills, fever, tinnitus and headache, and about one in five patients vomits
- The drug irritates the endothelium of the veins, and local thrombophlebitis is sometimes observed
- Intrathecal injections can cause neurotoxicity
- Topical applications cause a skin rash
- Liposome-encapsulated and lipid-complexed preparations cause fewer adverse reactions
how is Amphotericin B formulated
formulated as lyposome or with some other excipient
5-Flucytosine (5-Fluorocytosine)
- Synthetic, orally active, limited spectrum
- Usually administered with amphotericin for the treatment of systemic infections
- Converted into 5-fluorouracil in fungi
- Side effects are rare
- Resistance rises rapidly if used alone
-affects function and DNA RNA synthesis translation
Echinocandins
- Naturally occurring cyclic hexapeptides
- Inhibit the synthesis of 1,3-D-glucan
- Effective in the treatment of systemic infections, e.g. cryptococcal menigitis
- Poor oral bioavailability
- Remains protein bound as may be predicted
- Casponfungin only recently been licenced
Allylamines
- Synthetic agents, similar to naftifine
- Inhibit the synthesis of lanosterol
- Effective in the treatment of superficial mycoses
- Formulated for oral and topical use
- Amorolifine used as 1% solution in nail laquer
- Onychomycosis risk factors include diabetes
What inhibits ergosterol
Echinocandins
What inhibits lanosterol -> ergosterol
azoles
What drugs inhibit squalene -> lanosterol
Terbinafine
Naftifine
Amorolfine
Which drug interupts steroid synthese
Amphotericin
Which drug affects microtubule system
Griseofuluin
What inhibits DNA in nucleus
Flucytosine
enzyme that makes ergosterol for cell wall
aplha demethylase
