Antifungal Agents Flashcards Preview

Block 1 - Treatment And Prevention Of Illness > Antifungal Agents > Flashcards

Flashcards in Antifungal Agents Deck (26)
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1
Q

Fungi

A

• 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

2
Q

Types of Fungal Infections (Mycoses)

A
  • 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
3
Q

Targets for Antifungal Therapy

A
  • echinocandins
  • azoles
  • terbinafine, naftifine, amorolfine
  • griseofuluin
  • flucytosine
4
Q

Key Classes of Antifungals

A
  • 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
Q

• 5-Flucytosine is also

A

a useful chemotherapy agent

6
Q

• Imidazoles vs. triazoles

A

• 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
7
Q

Imidiazole Antifungals

A
  • 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
8
Q

Triazole Antifungals

A
  • 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
9
Q

Azoles: Drug Interactions

A

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
10
Q

Resistance to Azoles

A
  • 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

11
Q

Polyene Antifungals

A
  • 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
12
Q

humans do not have..

A

humans do not have ergosterol in their cell walls

13
Q

Amphotericin B key region

A

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

14
Q

Amphotericin B

A

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

15
Q

Amphotericin B: Side Effects

A
  • 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
16
Q

how is Amphotericin B formulated

A

formulated as lyposome or with some other excipient

17
Q

5-Flucytosine (5-Fluorocytosine)

A
  • 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

18
Q

Echinocandins

A
  • 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
19
Q

Allylamines

A
  • 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
20
Q

What inhibits ergosterol

A

Echinocandins

21
Q

What inhibits lanosterol -> ergosterol

A

azoles

22
Q

What drugs inhibit squalene -> lanosterol

A

Terbinafine
Naftifine
Amorolfine

23
Q

Which drug interupts steroid synthese

A

Amphotericin

24
Q

Which drug affects microtubule system

A

Griseofuluin

25
Q

What inhibits DNA in nucleus

A

Flucytosine

26
Q

enzyme that makes ergosterol for cell wall

A

aplha demethylase