Anti-Fungals

Front 1

What are the different anti-fungal drugs available?

Back 1

Polyenes: Amphotericin B, Nystatin

Azoles: Imidazoles- Clotrimazole, miconazole;

Triazoles- Itraconazole, Voriconazole,

Fluconazole

Echinocandins: Caspofungin

Pyramidine analogue: Flucytosine

Topical meds: Terbinafine, clotrimazole, miconazole

Front 2

What is the mode of action of amphotericin B?

Back 2

Binds to ergosterol, destroying integrity of fungal cell membrane

Front 3

How do fungi gain resistance to amphotericin B?

Back 3

- Modify ergosterol to decrease binding affinity

- Decrease membrane concentration of ergosterol

Front 4

Describe the pharmacokinetics of amphotericin B.

Back 4

A: Poor oral bioavailability, administer by IV, eye drops, intra-articular way

D: Widely distributed but poor CSF entry

M: Metabolised by unknown pathway

E: Excreted in urine over several days (Slow excretion)

Front 5

Give the clinical uses of amphotericin B.

Back 5

- As eye drops: To treat fungal keratitis

- As intra-articular administration: to treat fungal arthritis

- As intrathecal administration: To treat fungal meningitis

- Used for invasive aspergillosis, systemic candidiasis and histoplasmosis

Front 6

List the toxicity effects of amphotericin B.

Back 6

- Nephrotoxicity ***

- Hypokalemia

- Reduced erythropoietin production -> normochromic normocytic anaemia

- Thrombophlebitis ***

- Fever, chills, vomitting

- Bone marrow suppression

Front 7

What is the precaution to take note of when giving IV amphotericin B?

Back 7

- Start with small dose of 1mg/50ml dextrose first

- If no adverse reaction, infuse slowly over 2-4h

Front 8

What are the important drug interactions to take note of when using amphotericin B?

Back 8

- Digoxin. (due to hypokalemia as a result of amphotericin B)

- Other nephrotoxic drugs like aminoglycosides, NSAIDs, cyclosporine

Front 9

What is the mode of action of nystatin?

Back 9

Binds to ergosterol, forming pores in fungal cell membrane

Front 10

What are the clinical uses of nystatin?

Back 10

CANDIDIASIS!

- Oral (by gargle)

- Vaginal (by pessary)

Front 11

What is the mode of action of azoles?

Back 11

Binds to lanosin-a-demethylase, to inhibit demethylation of lanosterol to ergosterol -> affects cell wall synthesis

Front 12

What is the spectrum of activity of itraconazole?

Back 12

Systemic fungi:

Aspergillus, candida, histoplasma, blastomyces, trichophyton

Front 13

Describe the pharmacokinetics of itraconazole.

Back 13

A: Oral route, lowest bioavailability of all the azoles, best absorbed with food

D: Poor entry into CSF

M: Extensive hepatic metabolism

E: Urinary excretion

Front 14

What are the clinical uses of itraconazole?

Back 14

Superficial infections:

- For dermatophytosis and onychomycosis (trichophyton, epidermophyton)

Subcutaneous infections:

- For sporotrichosis (sporothrix schenckii)

Systemic infections:

- For candida, aspergillus, blastomyces, histoplasma

Front 15

What are the toxicity effects of using itraconazole?

Back 15

- GIT disturbances

- Rashes

- Headache

- Cardiac suppression

- Hepatotoxicity

Front 16

What are the significant drug interactions with itraconazole?

Back 16

- itself is a CYP inhibitor

- Proton pump inhibitors, antacids, H2 antagonists cause decrease absorption of itraconazole

Front 17

Describe the pharmacokinetics of voriconazole.

Back 17

A: Good oral bioavailability, can be administered by IV also

D: Enters CSF well

M: Extensively metabolised by liver

E: Excreted in urine

Front 18

What are the clinical uses of voriconazole?

Back 18

- Candidemia

- Invasive aspergillosis

Front 19

What are the toxicity effects of voriconazole?

Back 19

- GIT disturbances

- Rash

- Hepatitis

- Acute transient visual disturbances

(eg changes in colour perception, blur vision, photophobia)

Front 20

What is the contraindication of using voriconazole?

Back 20

Cannot be used for pregnant women

Front 21

What are the important drug interactions with voriconazole?

Back 21

- Itself is CYP inhibitor, avoid with use of other powerful CYP inducers

Front 22

What are the clinical uses of fluconazole?

Back 22

- Candidemia -> IV route

- Oral candidiasis -> Oral route

- Cryptococcal meningitis

Front 23

Describe the pharmacokinetics of fluconazole.

Back 23

A: Good oral bioavailability, administered by IV route also

D: Widely distributed, enters CSF well

M: Minimal metabolism by liver

E: Excreted in urine

Front 24

List the toxicity effects of fluconazole.

Back 24

- GIT disturbances

- Rashes (Stevens-Johnson Syndrome)

- Headache

Front 25

What are the important drug interactions with fluconazole?

Back 25

It is a CYP inhibitor itself, interacts with other drugs (cause their plasma conc to rise)

Front 26

What is the mode of action of caspofungin?

Back 26

Inhibits B-glucan synthase

Front 27

Describe the pharmacokinetics of caspofungin.

Back 27

A: IV only due to poor oral bioavailability

D: Widely distributed but cannot enter CSF

M: Gradual metabolism over time

E: Excreted in urine and bile

Front 28

What are the clinical uses of caspofungin?

Back 28

- Used in invasive aspergillosis as salvage treatment if amphotericin B fails

- Candidemia/candidiasis in immunocompromised patients

Front 29

List the toxicity effects of caspofungin.

Back 29

Generally well-tolerated.

- GIT disturbances (vomitting)

- Fever

- Rashes

- Histamine-like reactions (flushing)

- Thrombophlebitis

Front 30

What are the important drug interactions with caspofungin?

Back 30

- Cyclosporine: can increase risk of hepatotoxicity

- Interaction with CYP inducers reduces plasma levels of caspofungin

Front 31

What is the mode of action of flucytosine?

Back 31

A pyrimidine analogue.

1. Converted by cytosine deaminase to form 5-fluorouracil

2. 5-fluorouracil converted to 5-fluoro-dUMP -> inhibits thymidylate synthase -> inhibits DNA synthesis

3. 5-fluoro-dUMP converted to 5-fluoro-dUTP -> inhibits RNA processing and translation

Front 32

Describe the pharmacokinetics of flucytosine.

Back 32

A: Good oral bioavailability, only oral administration

D: Widely distributed, enters CSF well

E: 90% excreted renally

Front 33

What are the clinical uses of flucytosine?

Back 33

Can be combined with amphotericin B to treat candida/cryptococcal meningitis.

--> therefore dose for amphotericin B can be reduced, so reduce nephrotoxicity

Front 34

List the toxicity effects of flucytosine.

Back 34

- Myelosuppression

- Hepatotoxicity

Front 35

What are the important drug interactions with flucytosine?

Back 35

- Use with nephrotoxic drugs (e.g. amphotericin B)

- Flucytosine itself is CYP inhibitor

Front 36

What is the mode of action of terbinafine?

Back 36

Inhibits squalene epoxidase so that squalene accumulates, which is fungicidal

Front 37

What are the clinical uses of terbinafine?

Back 37

For dermatophytic infections.

Front 38

What are the clinical uses of clotrimazole and miconazole?

Back 38

- Clotrimazole: For skin and vulvovaginal infections

- Miconazole: For oral thrush, vulvovaginal candidiasis, tinea infections.