Antiviral drugs

Question 1

2 Influenza drugs:

Answer 1

Zanamivir, oseltamivir

Question 2

drug for RSV, Hepatitis C:

Answer 2

Ribavirin

Question 3

Herpes viruses drug:

Answer 3

Acyclovir

Question 4

3 CMV Drugs:

Answer 4

Ganciclovir • Foscarnet • Cidofovir

Question 5

Zanamivir/Oseltamivir inhibit:

Answer 5

neuraminidase • Enzyme that cleaves sialic acid from glycoproteins • Required step in exit from infected cells

Question 6

Ribavirin Inhibits 2 things:

Answer 6

RNA polymerase • Triphosphorylated by cellular kinase enzymes • Binds RNA polymerase, prevents binding correct nucleotides

*guanosine analog*

Inhibits IMP dehydrogenase •Used to synthesize guanine nucleotides • Inhibited by Ribavirin • Decreases pool of available guanine nucleotides

Question 7

Ribavirin • Two main modern uses & side effects:

Answer 7

RSV in children

Hepatitis C • Often with interferon •

Key side effect: Hemolytic anemia • Drug accumulates in RBCs • Drug phosphorylation → relative ATP deficiency • Hemolytic anemia in ~10% patients • Can be severe • Highly teratogenic

Question 8

Acyclovir inhibits:

phosphorylation:

Answer 8

Inhibitor of herpes virus DNA polymerase • Mimics guanosine → terminates chain growth

Phosphorylated by herpes virus thymidine kinase • Becomes acyclovir monophosphate • Only occurs in infected cells (targeted effect) • Monophosphate → triphosphate by cellular enzymes

Question 9

3 Acyclovir Resistance mechanisms:

Answer 9

↓ viral thymidine kinase

Altered viral thymidine kinase

Altered viral DNA polymerase (↓ binding acyclovir triphos.)

Question 10

Acyclovir type drugs:

Answer 10

Famciclovir: Similar mechanism • Longer half-life (lower dose can be used)

Valacyclovir: Pro-drug, converted to acyclovir • Greater bioavailability (lower dose can be used)

All 3 drugs generally well tolerated

Acyclovir: Nephrotoxicity (IV form) • Crystalizes in urine • Given with IV fluids

Question 11

Acyclovir effective for:

Answer 11

HSV-1, HSV-2, and VZV

Uses:

Genital herpes

Herpes labials

Herpes encephalitis

Herpes zoster

• Sometimes given for “suppressive” therapy

Question 12

3 key CMV Drugs:

all interfere with:

Answer 12

Ganciclovir • Foscarnet • Cidofovir

• All interfere with CMV DNA polymerase

Question 13

Ganciclovir

Answer 13

Similar mechanism to acyclovir (analog to guanosine) • Intracellular conversion by CMV viral kinase • Becomes ganciclovir 5’-monophosphate • Monophosphate → triphosphate by cellular enzymes • Acts as analog to deoxyguanosine triphosphate (dGTP) • Incorporation terminates chain growth

Question 14

Ganciclovir Major toxicity:

Answer 14

Bone marrow suppression especially leukopenia • Inhibits bone marrow DNA polymerase

Valganciclovir • Pro-drug • Converted to ganciclovir • Better bioavailability • Ganciclovir given primarily IV (poor bioavailability) • Oral valganciclovir preferred for oral dosing

Question 15

Foscarnet

Answer 15

• Pyrophosphate analog

Binds/inhibits viral DNA polymerase

Blocks cleavage pyrophosphate from triphosphates • Stops DNA chain elongation

Question 16

Foscarnet uses & side effects:

Answer 16

Uses: • CMV when Ganciclovir fails • Acyclovir-resistant HSV and VZV

Side effects • Nephrotoxicity (limiting side effect) • Chelates calcium (hypocalcemia) • Induces renal wasting of magnesium (hypomagnesaemia) • Seizures (often related to electrolytes)

Question 17

Cidofovir:

what is it?

phosphorylation:

inhibits:

main use:

main toxicity:

Answer 17

Nucleotide analog (cytidine) • Cellular phosphorylation • No viral kinase required

Inhibits viral DNA polymerase

Main use is CMV retinitis

Main toxicity is renal failure • Co-administer with saline • Probenecid (blocks renal tubular secretion of drug)

Question 18

Interferons

what are they:

uses:

Answer 18

Cytokines • Glycoproteins synthesized by infected cells • Numerous immunomodulatory effects •

Interferon α:

Hepatitis B and C

Kaposi sarcoma (HHV-8)