Pharmacology - Viral Infections

Front 1

Neuraminidase inhibitors

Back 1

- prevent release of virus
- Oseltamivir, Zanamivir

Front 2

Oseltamivir and Zanamivir

Back 2

- Effective against type A and type B influenza
- admin prior to exposure --> prevent infection
- admin w/in 24-48 hrs after infection --> modest effect
- MOA = analog/inhibitor of sialic acid substrate for neuraminidase --> inhibit release of virus

Front 3

Oseltamivir and Zanamivir - PK/AE

Back 3

PK
Oseltamivir - orally active prodrug (hydrolyzed in liver)
Zanamivir - NOT orally active (inhaled, intranasal)
AE
- Oseltamivir - GI discomfort, nausea (alleviated w/ food)
- Zanamivir - NO GI effects, Airway irritation (AVOID in severe asthma, COPD)

Front 4

Oseltamivir and Zanamivir - Resistance

Back 4

- less infective + virulent neuraminidase mutations identified

Front 5

Ion channel blockers

Back 5

- prevent uncoating of virus in the cell
- Amantadine and Rimantadine

Front 6

Amantadine and Rimantadine

Back 6

- Exclusively active on Influenza A virus
- MOA - Blocks viral membrane protein, M2 (H+ channel)
- channel is required for fusion of viral w/ cell membrane --> endosome (required for viral uncoating)
- "A man to dine" takes off his coat

Front 7

Amantadine and Rimantadine - PK

Back 7

- oral
- amantadine - widely dist, crosses BBB (rimantadine is NOT), NOT extensively metabolized and excreted into urine where it may accumulate
- Rimantadine IS metabolized and eliminated by the kidney

Front 8

Amantadine and Rimantadine - AE

Back 8

Amantadine - CNS: insomnia, dizziness, ataxia --> hallucinations, seizures

Rimantadine - fewer problems

Both - GI intolerance

Front 9

Amantadine and Rimantadine - Contraindications and Resistance

Back 9

CI: monitor in psychiatric pts, cerebral atherosclerosis, renal impairment, epilepsy

CI: PREGNANCY, NURSING

Resistance - Up to 50%; cross-resistance w/ other drugs also occurs

Front 10

Purine/pyrimidine analogs

Back 10

- prevent RNA/DNA synthesis
- Ribavirin

Front 11

Ribavirin

Back 11

- Active against broad spectrum of RNA and DNA viruses (eg RSV, HCV, Lassa fever)
- guanosine analog

Front 12

Ribavirin - MOA

Back 12

- converted to ribavirin-triphosphate --> inhibits guanosine triphosphate formation --> prevents viral mRNA capping --> inhibits RNA-dep RNA polymerase

Front 13

Ribavirin - PK

Back 13

- Oral, IV, aerosalized
- absorption increased if taken w/ fatty meal
- drug retention in all tissues except brain
- drug/metabolite eliminated in urine

Front 14

Ribavirin - AE/CI

Back 14

AE - dose-dependent transient anemia (can bind to RBC), elevated bilirubin

CI: PREGNANCY

Front 15

Treatment of Hepatic Viral Infections

Back 15

Interferons
- Interferon alpha, beta, gamma

Nucleotide/Nucleoside Analogs
- Lamivudine, Adefovir, Entecavir, Telbivudine

ALL inhibit RNA/DNA synthesis

Front 16

Interferons

Back 16

- Naturally occurring, inducible glycoproteins/cytokines, alpha and beta produced by man cell types, gamma by immune cells (T cells)
- MOA: Use innate immune response; DO NOT target viral gene products directly
- Inhibit RNA and DNA synthesis by activating/inducing protein expression that inhibit virus infection (eg PKR)

Front 17

Interferons - PK/AE

Back 17

PK
- NOT orally active (IV, subcut, intralesionally)
- cell uptake and met by liver and kidney --> little in plasma
- usually pegylated to improve PK profile

AE
- Flu-like (fever, chills, myalgias + GI disturbances)
- Fatigue + mental depression

Front 18

Interferons - Drug Interactions/Clinical Applications

Back 18

Drug Interactions
- interferes w/ hepatic drug metabolism --> toxic acc of theophylline
- may potentiate myelosuppression caused by zidovudine

Clinical App:
- interferon alpha: HCV, HBV, condyloma acuminata, hairy-cell leukemia, Kaposi's sarcoma
- interferon beta - MS

Front 19

Lamivudine, Adefovir, Entecavir, Telbivudine

Back 19

- must be phosphorylated to triphosphate (active) form

Front 20

Lamivudine

Back 20

- comp inhibits HBV DNA polymerase
- well absorbed orally + widely dist (half-life = 9h)
- excreted unchanged in urine
- well tolerated

Front 21

Adefovir

Back 21

- incorp in viral DNA --> termination of DNA syn
- admin once daily, excreted in urine (45% active compound)
- discontinuation --> severe exacerbation of hepatitis (25%)
- used cautiously with renal dysfunction

Front 22

Entecavir

Back 22

- competes w/ deoxyguanosine triphosphate for viral reverse transcriptase
- effective against lamivudine-resistant strains of HBV
- very little metabolized
- renal function must be assessed and drugs w/ renal toxicity avoided
- monitor after discontinuation --> poss severe hepatitis

Front 23

Telivudine

Back 23

- NOT effective against HIV or other viruses
- either competes w/ endogenous thymidine triphosphate or incorporates into viral DNA --> terminate DNA chain elongation
- oral once a day
- eliminated unchanged by glomerular filtration

Front 24

Tx of Herpesvirus Infections

Back 24

- eg cold sores, viral encephalitis, genital infections
- herpes can form latent infection; available drugs are for REPLICATING VIRUS ONLY
- Purine/pyrimidine Analogs: Acyclovir, Cidofovir, Ganciclovir, Penciclovir, Famiclovir, Vidarabine, Trifluridine
- Fomivirsen
- Foscarnet

Front 25

Acyclovir

Back 25

- Prototypic antiherpetic therapeutic agent
- HSV Types 1 and 2, VZV, some EBV (HSV4)
- DOC IN HSV ENCEPHALITIS
- also used for genital herpes infections and prophylactically in IC and transplant pts

Front 26

Acyclovir - MOA

Back 26

- Guanosine analog
- Monophosphorylated by HSV/VZV thymidine kinase --> only infected cells susceptible
- Competes w/ dGTP; once incorp into DNA causes chain termination and INHIBITS VIRAL DNA POLYMERASE

Front 27

Acyclovir - PK

Back 27

- IV, oral, topical
- well dist (INCLUDING CSF)
- partially metabolized --> urine (can acc w/ renal failure)

Front 28

Acyclovir - AE/Resistance

Back 28

AE: depends on route of admin:
- topical = local irritation
- oral = headache, diarrhea, nausea, vomiting
- renal dysfunction at high doses

Resistance - **altered or deficient thymidine kinases** and DNA polymerases (most commonly in IC)
- cross resistance to other cyclovirs

Front 29

Cidofovir

Back 29

- HSV, adenovirus, CMV-induced retinitis in HIV/AIDS
- NOT phosphorylated by viral kinases
- REQUIRES ACTIVATION BY HOST CELL KINASES
- effective against HSV and Ganciclovir resistant orgs
- MOA: DNA chain terminator and DNA polymerase inhibitor

Front 30

Cidofovir - PK, AE, Resistance

Back 30

PK: IV, intravitreal, and topical
- must be co-admin w/ probenecid (blocks renal tubular secretion)

AE: nephrotoxicity

Resistance: mutations in viral DNA polymerase

Front 31

Ganciclovir

Back 31

- Valganciclovir = pro-drug w/ greater oral bioavailability
- Analog of acyclovir (8-20X activity against CMV)
- DOC FOR CMV RETINITIS + CMV PROPHYLAXIS IN IC
- MOA - phosphorylated by viral and cell kinases; DNA chain terminator and DNA polymerase inhibitor

Front 32

Ganciclovir - PK

Back 32

- IV, well dist (including CSF)
- excretion in urine via glomerular and tubular secretion
- valganciclovir undergoes rapid hydrolysis in intestine and liver --> ganciclovir

Front 33

Ganciclovir - AE/CI/Resistance

Back 33

AE: myelosuppression, severe, dose-dependent neutropenia

CI: PREGNANCY

Resistance: reduced intracellular phosphorylation (mutations in phosphotransferase) or mutations in viral DNA polymerase

Front 34

Famciclovir and Penciclovir

Back 34

- Famciclovir - pro-drug of penciclovir
- active against HSV-1,2 and VZV
- MOA: inhibit HSV DNA polymerase / chain terminator
- PK: Penciclovir - only topical (half life is 20-30 times acyclovir triphosphate); Famciclovir - oral
- AE: Headaches, nausea, diarrhea
- Resistance - Low occurrence clinically

Front 35

Vidarabine

Back 35

- Adenine analog
- effective against HSV, CMV, VZV
- limited to tx of IC pts w/ herpetic and vaccinal keratitis + HSV keratoconjunctivitis
- MOA: inhibits viral DNA synthesis after conversion to triphosphate
- PK - opthalmic ointment
- AE: superficial punctate keratitis, pain, photophobia

Front 36

Trifluridine

Back 36

- Thymidine analog
- Effective against HSV-1,2 and vaccina virus
- DOC FOR HSV KERATOCONJUNCTIVITIS AND RECURRENT EPITHELIAL KERATITIS
- MOA - incorporated into viral DNA causing fragmentation
- PK: ophthalmic ointment (too toxic for systemic use)
- AE: transient irritation of eye + palpebral (eyelid) edema

Front 37

Fomivirsen

Back 37

- Antisense oligonucleotide
- USED WHEN OTHER THERAPIES FOR CMV RETINITIS FAIL
- MOA - bind to CMV mRNA inhibiting CMV protein synthesis
- PK: intravitreally; long half-life
- AE: iritis, vitritis, changes in vision and changes in intraocular pressure

Front 38

Foscarnet

Back 38

- organic analog of inorganic pyrophosphate (does NOT require phosphorylation)
- "FOScarnet = pyroFOSphate analot"
- used for CMV retinitis in IC pts, acyclovir resistant HSV and CMV retinitis, gancyclovir-resistant CMV + VZV
- MOA: selectively inhibits virus-specific DNA polymerase and reverse transcriptase
- PK: IV (poor oral abs), widely dist including CNS

Front 39

Foscarnet: AE/Resistance

Back 39

AE
- Nephrotoxicity, hypocalcemia
- CNS: hallucinations, seizures

Resistance
- Point mutation in polymerase