Antiviral drugs

Question 1

Amantadine and rimantadine

Answer 1

• Block the M2 protein (H+ ion channel) in envelope of influenza A (prevents, and treats w/in 48 hrs of onset)
• Prevents viral uncoating and thus inhibits transfer of nucleocapsid into host (only for influenza A)
• Amantadine is lipophilic and enters CSF, is unchanged before renal excretion (can cause renal toxicity in patients w/ renal failure). Also used in parkinson’s
• Amantadine can cause some CNS adverse effects: hallucinations, seizures in elderly/epileptics
• Rimantadine is less lipophilic (does not enter CSF as much) and is inactivated before renal excretion (ok for renal failure patients)
• Fewer CNS adverse effects
• Both are teratogenic (cat. C: risk-versus-benefit)

Question 2

Oseltamivir (tamiflu)

Answer 2

• Is a prodrug (ethyl ester) and an analog of sialic acid
• Converted to active carboxylate form in liver, excreted renally as active drug
• Inhibits NA on influenza A and B, which removes sialic acid residues form glycoproteins/lipids to allow viral release from the cell
• Comepetitively inhibiting NA leads to a block in the release of the virus from the cell surface (only prevents and treats influenza A & B, swine flu H1N1)
• Adverse effects: nausea, vomiting, teratogenic (cat. C)

Question 3

Ribavirin

Answer 3

• Prodrug that is a guanosine analog, activated by host cell kinases (nonselective)
• Ribivarin monophosphate inhibits host nz inosine monophosphate dehydrogenase, leading to inhibition of synthesis of GTP, viral RNA, and DNA
• Ribivarin triphosphate inhibits RNA polymerase of influenza A & B viruses (broad spectrum antiviral, more for RNA viruses)
• Administered by aerosol, oral, or IV (T1/2 in RBC= 40 days, T1/2 in tissues= 12 days)
• When given by inhalation can cause apnea, pneumothorax, cardiac arrest
• Oral or IV can cause hemolytic anemia (dose-limiting)
• Teratogenic (cat. X- never used)
• Used to treat respiratory syncytial virus in neonates (aerosol), lassa fever (IV), hepatitis C (oral) w/ INF-a2b

Question 4

Acyclovir

Answer 4

• Guanosine analog, prodrug that is first phosphorylated by herpes virus-encoded thymidine kinase
• Therefore is selective to virus-infected cells
• Host kinases phosphorylates to triphosphate
• Acyclovir triphosphate inhibits viral DNA polymerase and incorporates into viral DNA causing premature chain termination (lacks 3’ OH group needed for next nucleotide)
• Used topically, orally, IV. Enters CSF. Accumulates in patients w/ renal failure
• IV infusion may cause renal insufficiency or neurological toxicity
• Not teratogenic (cat. B)
• Used to treat HSV encephalitis, herpes genitalis, labials, zoster, varicella, prophylaxis (in IC)

Question 5

Vidarabine

Answer 5

• Analog of adenosine, prodrug activated by host kinases to triphosphate (not selective to virus-infected cells)
• Vidarabine triphosphate inhibits viral DNA polymerase and incorporates into viral DNA to terminate DNA chain (same mech. as acyclovir)
• Insoluble and requires large volumes of IV fluids administered simultaneously
• Rapidly deaminated (inactivated)
• Causes encephalopathy (headache, dizziness, hallucinations, coma) b/c deaminases are low in CNS
• Used for herpes keratitis (topical application, use acyclovir for systemic)

Question 6

Ganciclovir

Answer 6

• Guanosine analog, prodrug which is activated by viral thymidine kinase (HSV) or cytomegalovirus kinase via phosphorylation
• Host cell kinases phosphorylate to triphosphate
• Triphosphate form inhibits viral DNA polymerase (same as acyclovir), and incorporates into viral DNA but does not cause chain termination only slows rate of chain elongation (different from acyclovir)
• Administered IV, 90% is excreted through urine unchanged (decrease dose for renal insufficiency)
• It is activated in proliferating cells of bone marrow, causing leukopenia and thrombocytopenia
• Is teratogenic (cat. C)
• Used for Rx of cytomegalic retinitis