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
