Antivirals Flashcards
1
Q
Treatment of respiratory infections
A
Influenza A, B and RSV
- Neuramindase inhibitors: Oseltamivir, Zanamivir
- Inhibitors of viral uncoating: Amantadine, rimantadine
- Synthetic Guanosine Analog: Ribavirin
2
Q
Oseltamivir, Zanamivir
A
- Neuraminidase inhibitor
- Effective against BOTH Type A and Type B Influenza
- Administered prior to exposure as prophylaxis
- Administered within 24 - 48h after infection drugs have modest effect on symptoms
- Oseltamivir indicated for influenza A & B Pt w severe asthma
MOA
- Analogs / inhibitors of sialic acid substrate for neuraminidase
- Inhibit release of virus
PK
- Oseltamivir: orally active prodrug (hydrolyzed in liver)
- Zanamivir: NOT orally active (inhaled, intranasal)
- Indicated for children > 7 yo
3
Q
Neuramindase - Adverse
A
- Oseltamivir: GI discomfort, nausea (alleviated when taken with food)
- Zanamivir: **airway irritation (avoid in severe asthma, COPD) **
Resistance: Less infective & virulent neuraminidase mutations identified
4
Q
Amantadine, Rimantadine
A
- ion channel blockers -> blocks uncoating
- EXCLUSIVELY ACTIVE ON INFLUENZA A VIRUS
- Equally effective in prophylaxis and treatment (70- 90%)
- Since 2006 not recommended as first-line treatments due to resistance
MOA
- Block viral membrane protein, M2 (H+ channel)
- Channel is required for fusion of viral with cell membrane to endosome (requirement for viral uncoating)
PK
- Oral
- Amantadine is widely distributed & crosses BBB (Rimantadine is NOT), not extensively metabolized & excreted into urine where it may accumulate
- Rimantadine IS metabolized before elimination in urine
Resistance
- Up to 50% individuals are naturally resistant
- Cross-resistance between drugs occurs
5
Q
Ion channel blockers - Adverse
A
- Amantadine: CNS (~10%) (insomnia, dizziness, ataxia leading to hallucinations, seizures)
- Rimantadine: fewer problems
- Both: GI intolerance
Contraindications
- Amantadine should be monitored in psychiatric patients, cerebral atherosclerosis, renal impairment, epilepsy
- Pregnancy, nursing (FDA Category C): not recommended in both pregnancy and nursing
6
Q
Ribavirin
A
- synthetic guanosine analog
- Active against broad spectrum of RNA & DNA viruses (eg, RSV, HCV, Lassa fever)
- Commonly used in combination with interferon alpha for the treatment of HCV
MOA
- Converted to ribavirin-triphosphate which inhibits guanosine triphosphate formation and prevents viral mRNA capping.
- Inhibits RNA-dependent RNA polymerase resulting in inhibition of viral protein synthesis
PK
- Oral, IV, & aerosolized
- Distribution significantly prolonged in RBC (16-40 days)
7
Q
Ribavirin - Adverse
A
- Dose-dependent transient anemia (can bind to RBC)
- GI (nausea, anorexia)
- CNS (fatigue, headache, insomnia)
Contraindications
- Pregnancy (FDA Category X); Never give to pregnant women or male Pt living with a pregnant women due to aerosolization
- Negative pregnancy tests required before treatment and monthly during treatment of female patients or female partners of male patients
8
Q
Hepatitis viral infection Rx
A
- Interferon: Interferon alpha
- **Nucleotide / Nucleoside Analogs: **Lamivudine, Entecavir, Ribavirin
- Protease Inhibitors: Boceprevir, Telaprevir
9
Q
Interferon alpha
A
- Naturally occurring, inducible glycoproteins / cytokines
- alpha and beta produced by many cell types, gamma by immune cells (T cells)
MOA
- Use innate immune response.
- DO NOT target viral gene products directly
- Inhibit RNA & DNA synthesis by activating / inducing protein expression that inhibit virus infection eg, PKR
Clinical applications
- HCV (in combination with ribavirin)
- HBV, condyloma acuminata, hairy-cell leukemia, Kaposi’s sarcoma
PK
- Not orally active (IV, subcutaneously, intralesionally)
- Cellular uptake and metabolism by liver & kidney
- Usually pegylated to improve PK profile
10
Q
Interferon alpha - Adverse & Interactions
A
- Flu-like (fever, chills, myalgias & GI disturbances)
- Fatigue & mental depression
Interactions
- Interferes with hepatic drug metabolism. Can cause toxic accumulation of theophylline; due to small therapeutic window
- May potentiate zidovudine induced myelosuppression
11
Q
Lamivudine
A
- Nucleoside/nucleotide analogs
- Must be phosphorylated by cellular enzymes to triphosphate (active) form
- Actions are suppressive rather than curative
Clinical applications: Effective against hepatitis B and HIV
MOA
- Triphosphate form inhibits HBV and HIV reverse transcriptase
- Monophosphate form is incorporated into DNA (by HBV polymerase) resulting in chain termination
- Well tolerated (headache, dizziness, GI complaints)
12
Q
Entecavir
A
- Nucleoside/nucleotide analogs
- Must be phosphorylated by cellular enzymes to triphosphate (active) form
- Actions are suppressive rather than curative
Clinical applications: Effective against lamivudine-resistant strains of HBV & HIV
MOA
- Phosphorylated form competes with natural substrates for viral polymerase.
- Subsequent inhibition of polymerase blocks reverse transcriptase activity
- Monitor after discontinuation in case of exacerbation of severe hep
13
Q
Boceprevir, Telaprevir
A
- Used in the treatment of HCV in adult patients who have been previously untreated or failed treatment with interferon alpha and ribavirin
- Administered in combination with interferon alpha and ribavirin
MOA: Bind reversibly to nonstructural protein 3 (NS3) serine protease and inhibit replication of HCV
14
Q
Protease inhibitors - Adverse
A
- fatigue
- anemia
- nausea
- headache
- dysgeusia
15
Q
Herpes rx
A
- Herpes can form latent infection. Available drugs are for replicating virus only (useless during viral dormant part of lifecycle)
- Purine / Pyrimidine Analogs: Acyclovir, Valacyclovir, Cidofovir, Ganciclovir, Valganciclovir, Penciclovir, Trifluridine
- Foscarnet
16
Q
Acyclovir
A
- Prototypic antiherpetic therapeutic agent
- Activity against: herpes simplex virus (HSV) Types 1 and 2, varicella-zoster virus (VZV) & some Epstein- Barr (HSV4) infections
- TREATMENT OF CHOICE IN HSV ENCEPHALITIS
- Commonly used for genital herpes infections & prophylactically in immunocompromised and transplant patients
- CMV is resistant at clinically achievable levels (does not encode thymidine kinase)
- Valacyclovir (Val = more bioavailable): prodrug of acyclovir
MOA
- Requires 3 phosphorylation steps for activation
- Monophosphorylated by herpes virus-encoded enzyme (thymidine kinase)
- Host cell enzymes complete phosphorylation to di- and triphosphate forms
- Competes with dGTP; once incorporated into DNA causes chain termination & inhibition of viral DNA polymerase
Resistance
- Resistance is rare in immunocompetent host
- Cross resistance to other ‘cyclovirs’ does occur
- Occurs by:
- Altered or deficient thymidine kinases
- Altered viral DNA polymerase with decreased affinity for acyclovir
Resistance
- IV, oral or topical
- Valacyclovir has greater oral bioavailability than acyclovir
- Partially metabolized thus can accumulate with renal failure
18
Q
Ganciclovir
A
- Valganciclovir = pro-drug with greater oral bioavailability
- Analog of acyclovir (8-20 x activity against CMV)
- Drug of choice for CMV retinitis & CMV prophylaxis in immunocompromised
MOA
- Phosphorylated by viral (UL97) and cell kinases
- DNA chain terminator & DNA polymerase inhibitor
Resistance
- Reduced intracellular phosphorylation
- Mutations in phosphotranferase (UL97), or viral DNA polymerase
PK
- Ganciclovir (IV)
- Valganciclovir (oral) undergoes rapid hydrolysis in intestine & liver to ganciclovir
- Excretion via urine
20
Q
Cidofovir
A
- Major use is treatment of CMV-induced retinitis in HIV/AIDS
- Not phosphorylated by viral kinases
- Requires activation by host cell kinases
- Effective against HSV & ganciclovir resistant HSV
MOA: DNA chain terminator & DNA polymerase inhibitor
Resistance: Mutations in viral DNA polymerase
PK:
- IV, intravitreal & topical
- Must be co-administered with probenecid (blocks renal tubular secretion)
22
Q
Penciclovir
A
- Active against HSV-1, 2 and VZV
- Used for the topical treatment of HSV (cold sores)
MOA
- Monophosphorylated by viral thymidine kinase
- Further phosphorylation occurs to give active triphosphate form
- Inhibit HSV DNA polymerase / chain terminator
Resistance: Low occurrence clinically
PK: Topical only
24
Q
Trifluridine
A
- Effective against HSV-1, 2, and vaccina virus
- Drug of choice for HSV keratoconjunctivitis and recurrent epithelial keratitis
MOA: Triphosphate form incorporated into viral DNA causing fragmentation
PK:
- Ophthalmic ointment (too toxic for systemic)
- t1/2 = ~12 min (apply frequently)
26
Q
Foscarnet
A
- Organic analog of inorganic pyrophosphate
- DOES NOT require phosphorylation!!
- Used for CMV retinitis in immunocompromised patients, acyclovir-resistant HSV & CMV retinitis & ganciclovir-resistant CMV & VZV
MOA: Structural analog of the anion pyrophosphate that selectively inhibits the pyrophosphate binding site on viral DNA polymerases
Resistance: Point mutations in polymerase
PK: IV only
