Antiviral Drugs

Question 1

Respiratory Viral infection Treatment:
Infuenza A, B and Respiratory Syncytial Virus (RSV)

Neuraminidase inhibitors

Inhibitors of Viral uncoating

Synthetic Guanosine Analogue

Answer 1

Neuraminidase inhibitors:

• Oseltamivir
• Zanamivir

Inhibitors of Viral uncoating:

• Amantadine,
• Rimantadine

Synthetic Guanosine Analogue:
- Ribavirin

Question 2

Neuraminidase inhibitors - MOA

1. Effective against
2. When is administration best

Answer 2

Neuraminidase inhibitors: Oseltamivir, Zanamivir

• Analogs/inhibitors of sialic acid substrate for neuramindase*
• Inhibit release of virus
• Effective against BOTH Type A and B Infuenza*
• Administration is best prior to exposure as prophylaxis
• Admin within 24-48hrs after infection - modest effect on symptoms.

NOTE: 2015-2016 influenza season
- Osetamivir and zanamivir are the only twi agents recommended for use!!

Question 3

Neuraminidase Inhibitors PK/AE:

Answer 3

Oseltamivir: orally active prodrug (hydrolyzed in Liver)
Zanamivir: Not orally active (inhaled, intranasal)

AE:

• Oseltamivir: GI discomfort, nausea due to oral route (alleviated when taken with food)- 1 year up
• Zanamivir: airway irritation (avoid in severe asthma, COPD)- 7 years up

Question 4

Ion channel blockers MOA

1. Effective against
2. When is administration best

Answer 4

Amantadine - widely distributed and crosses BBB not extensively metabolized and excreted into urine where it may accumulate
Rimantadine - not widely distributed, metabolized and eliminated in urine.
- Block viral membrane protein, M2 (H+ channel)
- channel is required for fusion of viral with cell
membrane to endosome (requirement for viral uncoating)
- oral
1. Exclusively active against Influenza A virus
2. Equally effective in prophylaxis and treatment

NOT effective for treatment of current strains and not. used

Question 5

Ion channel blockers AE/CI:

Answer 5

Amantadine: CNS - insomnia, dizziness, ataxia, leading ti hallucinations, seizures
Rimantidine: fewer problems
Both: GI intolerance

CI:

• Monitor amantadine in psychiatric patients, cerebral atherosclerosis, renal impairment, epilepsy
• Pregnancy, nursing (FDA Category C)

upto 50% people are naturally resistant

Question 6

Purine/pyrimidine analogs MOA

1. Active against?
2. Combo’d with?

Answer 6

Ribavirin (Nucleoside anolgue GUANOSINE)
- Converted to Ribavirin-triphosphate which inhibits guanosine triphosphate formation nd prevents viral mRNA capping.

• Inhibits RNA-dependent RNA polymerase resulting in inhibition of viral protein synthesis
• Active against broad spectrum of RNA and DNA viruses (eg RSV, HCV, Lassa fever)
• used in combo with IFNa for HCV Tx.

Question 7

Ribavirin PK/AE

Answer 7

Oral IV and aerosolized
Distrbution significantly prolonged in RBC (16-40 days)

AE:

• Dose dependent transient hemolytic anemia (can bind to RBC).
• GI (nausea, anorexia)
• CNS (fatigue, headache, insomnia)

Question 8

Ribavirin CI:

Answer 8

Pregnancy (Cat. X) extrememly teratogenic

Question 9

Tx for Hepatic Viral infections Hep A,B,C,D, and E:
Interferon

Nucleotide/Nucleoside analogs

Protease Inhibitors

Answer 9

Interferon
- IFNa
Nucleotide/Nucleoside analogs
- Lamivudin, Entecavir, Ribavirin
Protease Inhibitors
- Boceprevir, Teleprevir

Question 10

INFa MOA:

Answer 10

• Naturally occuring, inducible glycoproteins/ cytokines
• Do Not target viral gene products directly
• Inhibit RNA and DNA synthesis by activating / Inducing protein expression that inhibit virus infection eg, PKR

Question 11

INFa PK/AE

Answer 11

Not orally active because its naturally occuring
uptake and metabolism by liver and kidney
usually pegylated to improve PK profile

AE:

• Flu like (fever, chills, myalgias and GI disturbances)
• Fatigue and mental depression
• interferes w/ hepatic drug metabolism. Can cause toxic accumulation of theophylline
• May potentiate zidovudine induced myelosuppression

Question 12

INFa

Clinical Applications: Diseases it treats?

Answer 12

• HCV (combo w/ ribavirin)

- HBV, condyloma acuminata, hairy cell leukemia, kaposi’s sarcoma

Question 13

Hepatic Anti-viral drugs

Nucleoside / Nucleotide Analogs

Answer 13

Lamivudine
Entecavir
- Must be phosphorylated by cellular enzymes to triphosphate (active) form.
- Actions are suppressive rather than curative

Question 14

Lamivudine
Active against:
MOA:

Answer 14

Hep B and HIV

• Triphosphate form inhibits HBV and HIV reverse transcriptase.
• Monophosphate for incorporates into DNA (by HBV polymerase) resulting in chain termination.
• well tolerated

Question 15

Entercavir
Active against:
MOA:

Answer 15

• effective against Lamivudine-resistant strains of HBV and HIV*
• phosporylated form competes w/ natural substrates for viral polymerase.
• Subsquent inhibition of polymerase blocks reverse transcriptase activity.

Monitor after discontinuation in case of exacerbation of severe hepatitis***

Question 16

Protease inhibitors

Answer 16

Boceprevir, Teleperir

• Tx of HCV in adult patients who have been previously untreatd or failed tx. w/ IFNa and ribavirin
• Combo’d wt, IFNa and ribavrin

MOA: Bind reversibly to nonstructural protein 3 (NS3) serine protease and inhibit replication of HCV

Question 17

Commonly reported AE reactions in adults due to protease inhibitors:

Answer 17

fatigue
anemia
nausea
headache
dysgeusia

Question 18

Tx of herpes viral infections

Answer 18

Herpes can form latent infection. Available drugs are for replicating virus only

Purine and pyrimidine analogs:
-ovir [acyclovir, valacyclovir, cidofovir, Ganciclovir, Valganciclovir, Penciclovir, Trifluridine

Foscarnet

Question 19

Acyclovir
DOC?
commonly used for?

Answer 19

Prototypic antiherpetic therapeutic agent
Activity against: herpes simplex virus (HSV) Types 1 and 2, VZV, EBV (HSV4).

DOC in HSV Encephalitis*

• Commonly used for genital herpes infections and prophylactically in immuncompromised and transplant patients.
• CMV is resistant at clinically achievable levels (does not encode thymidine Kinase)
• Valacyclovir = Prodrug of acyclovir

Question 20

Acyclovir MOA

Answer 20

• 3 phosphorylation steps for activation
• Monophosphorylated by herpes virus-encoded enzyme (thymidine kinase)
• Host cell enzymes complete phosporylation to di and triphosphate forms.
• Competes w/ GTP; once incorporated into DNA causes chain termination and inhibition of viral DNA polymerase

Resistance is rare in immunocompetent hosts. occurs by

• deficient thymidine kinases
• altered viral DNA polymerase w/ decreased affinity for acyclovir.

Question 21

Acyclovir - PK

Answer 21

• IV, oral or topical
• Valacyclovir has greater oral bioavailability than acyclovir
• Partially metabolized thus can accumulate w/ renal failure.

Question 22

Acyclovir AE

Answer 22

topical: local irritation
oral: headache, diarrhea, nausea and vomiting
IV: acute renal failure. Risk can be minimized by slow infusion and prioir hydration of patient.

Question 23

Gancyclovir

DOC?

Answer 23

• Valganciclovir = pro-drug w/ greater oral bioavailability
• analog of acyclovir (8-20 X activity against CMV)
• DOC for CMV retinitis and CMV prophylaxis in immunocompromised

MOA:
Phosphorylated by viral (UL97) and cell kinases
DNA chain terminator and DNA polymerase inhibitor

Question 24

Gancyclovir PK

Answer 24

Gancyclovir (IV)
Valgancycovir (oral) undergoes rapid hydrolysis in intestines and liver to gancyclovir
Urine excretion

Question 25

Gancyclovir AE/CI

Answer 25

Myelosuppresion Severe dependent neutropenia CI: Pregancy (FDA Cat. C)

Question 26

``` Cidofovir whats special about it? Major use? Activation? MOA? ```

Answer 26

Special because does not require phosphorylation by viral kinases. - Major use is tx. of CMV-induced retinitis in HIV/AIDS - Require activation by host cell kinases - effective against HSV and gancyclovir resistant HSV. MOA: - DNA chain terminator and DNA polymerase inhibitor

Question 27

Cidofovir PK/AE

Answer 27

IV, intravitreal and topical must be co-administered with probenecid (blocks renal tubular secretion)--> increased time for effects AE: Nephrotoxicity

Question 28

Penciclovir

Answer 28

Active against HSV 1-2 and VZV (cold sores) | Used for the topical tx of HSV (cold sores)

Question 29

Penciclovir | MOA?

Answer 29

penciclovir MOA: monophosporylated by viral thymidine kinase - further phosphorylation occurs to give active triphosphate form. - Inhibits HSV DNA polymerase/ chain terminator - active against HSV-1, 2 and VZV - Used for the topical tx. of HSV (cold sores)

Question 30

Penciclovir PK/AE

Answer 30

topical only AE: Dermatologic: mild erythema

Question 31

Trifluridine DOC MOA?

Answer 31

Effective against HSV-1, 2 and vaccina virus. DOC for HSV keratoconjunctivitis and recurrent epithelial keratitis MOA: Triphosphate form incorporated into viral DNA causing fragmentation

Question 32

Trifluridine - PK/AE

Answer 32

``` Ophthalmic ointment (too toxic for systemic) t1/2=12min (apply frequently) ``` AE: Transient irritation of eye and palpebral (eyelid) edema

Question 33

Foscarnet

Answer 33

Organic analog of inorganic pyrophosphate Does not require phosphorylation!! Used for CMV retinitis in immunocompromised patients, acyclovir-resistant HSV and SMV retinitis and gancilovir-resistant CMV and VZV.

Question 34

Fodscarnet MOA | resistance?

Answer 34

Structural analog of anion pyrophosphate that selectively inhibits the pyrophosphate binding site on viral DNA polymerases resistance: point mutation in polymerase

Question 35

Foscarnet PK/AE

Answer 35

IV only -LAST RESORT AE: Nephrotoxicity* Electrolyte disturbances (Ca+2, Mg+2, K+, PO4)* Anemia Genital ulceration (mainly men) CNS: Hallucinations, seizures, headache (25%)