Antivirals & Antifungals

Question 1

What is an NRTI and what kind of molecules are they

Answer 1

Nucleoside Reverse Transcriptase Inhibitors

Pyrimidine analogues (Thymidine and Cytosine)

Purine analogues (Adenine and Guanidine)

Question 2

What are the NRTI Pyrimidine analogues?

Answer 2

Thymidine analogues- Zidovudine

Cytosine analogues- Lamivudine

Question 3

What are the NRTI Purine anologues?

Answer 3

Adenine analogues - Tenofovir

Guanidine analogues - Abacavir

Question 4

What are NNRTIs?

Answer 4

Non-nucleotide reverse transcriptase inhibitors

eg. Efavirenz, Nevirapine

Question 5

What are PIs

Answer 5

Protease inhibitors

Question 6

What is HAART?

Answer 6

Highly Active Antiretroviral Therapy

Question 7

What is Aciclovir used to treat and what is its mechanism of action?

Answer 7

Herpes Simplex Virus (HSV)
Varicella Zoster Virus (VZV)

Phosphorylated by thymidine kinase to make a nucleoside analogue

Question 8

What is Ganciclovir used to treat?

Answer 8

Cytomegalovirus

Question 9

What are Oseltamivir and Zanamavir used to treat?

Answer 9

Influenza

Question 10

What is Ribavirin used to treat ?

Answer 10

Hepatitis C

Human respiratory syncytial virus (RSV)

Question 11

What are Interferons used to treat?

Answer 11

Hepatitis C virus

Hepatitis B virus

Question 12

Where is ergosterol found and what is its function?

Answer 12

Found in fungal cell membranes

Required for normal growth and function of the fungal cell wall

Question 13

What is the pathway for ergosterol synthesis and what two enzymes are involved?

Answer 13

Squalene –1–> Lanosterol –2–> Ergosterol

1 = Squalene epoxidase
2 = Lanosterol 14alpha demethylase

Question 14

What makes up fungal cell walls?

Answer 14

Mannan
β-1,3-glucans
Chitin

Question 15

What are the 4 main antifungal classes?

Answer 15

Polyenes
Allylamines
Azoles
Echinocandins

Question 16

What is the mechanism of action of the Polyenes? with examples

Answer 16

They associate with ergosterol to form pore-like molecular aggregates in the cell membrane.
Leads to loss of membrane integrity and leakage of K+

eg. Amphotericin B, Nystatin

Question 17

What is the spectrum of Amphotericin B and its potential adverse effects?

Answer 17

Most fungi of medical importance. Used systemically for severe infections.
eg. Aspergillus spp., Candida spp., Cryptococcus spp.

Allergic reactions
Nephrotoxicity - Pores are formed in ergosterol-free membranes

Question 18

How is the nephrotoxicity of amphotericin B reduced?

Answer 18

Lipid associated Amphotericin B (AmB)

eg. Liposomal AmB (L-AmB)

Question 19

What is the clinical use for Nystatin?

Answer 19

It is not absorbed orally and is too toxic for systemic use

Superficial infections
eg. oral/vaginal candidiasis

Question 20

What is the mode of action of Allylamines? with example

Answer 20

Prevent ergosterol synthesis by
Inhibiting Squalene epoxidase

eg. Terbinafine

Question 21

What is the clinical use for Allyamines and what are their adverse effects?

Answer 21

Dermatophyte infections (superficial fungal infections)

Topical use: Athletes foot (tinea pedis), tinea corporis, tinea cruris

Systemic (oral) use: Scalp ringworm (tinea capitis), onychomycosis

Liver toxicity

Question 22

What do the Azoles have in common?

Answer 22

Azoles contain a 5-membered azole ring

Imidazoles = Two nitrogen atoms
eg. Clotrimazole

Triazoles = Three nitrogen atoms
eg. Fluconazole, Itraconazole, Voriconazole

Question 23

What is the Azoles mode of action?

Answer 23

Prevent ergosterol synthesis
Inhibit Lanosterol 14α-demethylase

Build up of non-ergosterol 14α-sterols in cell membrane

Question 24

What are the adverse effects of Azoles?

Answer 24

Hepatotoxicity
Imidazoles more toxic than triazoles

Drug interactions
Inhibition of cytochrome P-450 enzymes
Increases concentration of all drugs metabolised by Cy P-450

Question 25

What are Imidazoles used for clinically?

Answer 25

Superficial infections (topical administration)

Candidiasis - Clotrimazole

Question 26

What are Triazoles used for clinically?

Answer 26

Systemic infections (oral/parenteral administration)

Aspergillosis - Itraconazole, if ineffective then Voriconazole

Candidiasis - fluconazole

Question 27

What is the antifungal spectrum of Fluconazole?

Answer 27

Limited to yeasts

eg. Candidiasis

Question 28

What is the antifungal spectrum of Itraconazole and Voriconazole?

Answer 28

Yeasts and Aspergillus spp.

Question 29

What is the antifungal spectrum of Posaconazole and Isavuconazole?

Answer 29

Yeasts, Aspergillus spp. and Mucoraceous moulds

Question 30

What is the mode of action of Echinocandins? with examples

Answer 30

Inhibition of β-1,3-glucan synthase
Causes construction of severely abnormal cell wall

eg. Anidulafungin, Caspofungin, Micafungin

Question 31

What is the spectrum of activity of Echinocandins, their adverse effects and clinical use?

Answer 31

Echinocandins sypectrum:
Aspergillus and Candida spp.
Misses certain moulds and Cryptococcus spp.

It has minimal adverse effect eg. rash, vomiting

For systemic infections, parenteral only

Question 32

What is 5-flurocytosine and why does it have selective antifungal toxicity?

Answer 32

5-flurocytosine is a synthetic analogue of cytosine

Entry into cell requires fungal cytosine permease

Converted to 5-fluorouracil and 5-fluorodeoxyuridine monophosphate
Inhibits RNA/protein synthesis and DNA synthesis

Question 33

What is the spectrum of activity for 5-flurocytosine and what are its adverse effects?

Answer 33

Yeasts only
Candida and Cryptococcus spp.

Bone marrow suppression
Selective toxicity is incomplete

Question 34

What is the clinical use for 5-flurocytosine?

Answer 34

Cryptococcal meningitis

in combination with AmB

Question 35

Which antifungals require therapeutic drug monitoring?

Answer 35

Itraconazole - to make sure at threshold dosage

5-fluorocytosine - to make sure not at bone marrow toxic levels

Voriconarozle - to make sure at threshold dosage and not toxic to liver