L35- Antiviral Drugs Flashcards
besides HIV and its associated HAART, list the common viral infections where antiviral therapy is employed
1) Respiratory Viruses: influenza A/B (+ RSV)
2) Hepatitis: B, C
3) Herpes: 1/2, 5 (CMV)
list the drugs for respiratory viral infections
- neuraminidase inhibitors
- endonuclease inhibitors
- synthetic guanosine analog
previously adamantanes
(1) are anti-viral drugs previous drugs used to treat respiratory viral infections- include agents. (2) was the primary clinical use, with (3) mechanism. (4) was the main reason that prompted its discontinued use. (5) are the AEs for (1).
1- Adamantanes: amantadine, rimantadine
2- influenza A Tx and prevention
3- prevents uncoating of viral binding
4- high rates of resistance
5- GI upset, nervousness, light-headedness, insomnia, anorexia, nausea, livedo reticularis
In the release of virons from infected cells, (1) on the virus is bound to (2) on the cell surface. (3) is then used to cleave this interaction, specifically (2) in order to release the virus. (4) have a (5) shape in order to prevent the release of viruses from infected cells.
1- hemagglutinin
2- sialic acid receptor
3- neuraminidase
4- neuraminidase inhibitors
5- sialic acid analog or substrate for neuraminidase (to block enzymatic function)
list the neuraminidase inhibitors
peramivir (IV)
oseltamivir (oral)
zanamivir (intranasal)
neuraminidase inhibitors:
- used to treat and prevent (1)
- best for treatment if given in (2) time-frame in order to have (3) effects
1- influenza A, B (prophylaxis and Tx)
2- first 24-48hrs of Sxs
3- shorten illness duration
______ is the IV neuraminidase, include AEs
peramivir:
- pruritus, skin peeling
- myalgia, fever, chills
- cough
- GI discomfort
______ is the oral neuraminidase, include AEs
oseltamivir:
-GI upset —- take with meals
______ is the intranasal neuraminidase, include AEs
zanamivir:
-airway irritation
Endonuclease inhibitors:
- functions in order to prevent (1)
- (2) clinical uses (include restriction)
- (3) AEs
Baloxavir Marboxil
1- viral gene transcription
2- prevents and treats influenza A, B
3- diarrhea, bronchitis
list the endonuclease inhibitors and describe its mechanism
Baloxavir Marboxil:
- prodrug is hydrolized into baloxavir
- -> inhibits endonuclease via selective binding of polymerase acidic protein (PA), which is required for gene transcription
list the guanosine analogs and describe its mechanism
Ribavirin, converted to ribavirin-triphosphate:
-inhibits RNA-dep. RNA poly –> inhibition of viral synthesis
-inhibits guanosine triphosphate formation + prevents viral mRNA capping
Guanosine Analogs:
- (1) are the clinical uses
- (2) is the route of administration
- (3) briefly describe distribution issue
(ribavirin)
1- influenza A/B, parainfluenza, *RSV, *HCV, lassa fever
2- IV, oral, aerosolized
3- prolonged in RBCs, 16-40 days (intracellular sequestering)
list the AEs and contraindications for guanosine analogs
(ribavirin)
- hemolytic anemia (10-20%)
- fatigue
- CNS: HA, insomnia
- GI: nausea, anorexia
Contraindications: pregnancy or males with pregnant partners
list the drugs for Hepatitis B infections
Interferon (α)
Nucleo-side/tide analogs
describe the mechanism of Interferon in the treatment of HBV and HCV
i) IFN binds receptor
ii) induces PKR (protein kinase R)
iii) induction of specific protein synthesis
iv) specific proteins inhibit RNA and DNA synthesis
list all the uses of IFN-α
-chronic HBV, HCV, in combination with ribavirin (guanosine analog)
- condyloma acuminata
- hairy cell leukemia
- Kaposi’s sarcoma
- renal cell carcinoma
- malignant melanoma
IFN-β is used clinically to treat (1)
IFN-γ is used clinically to treat (2)
β- MS
γ- chronic granulomatous disease
IFN-α AEs
- flu-like Sxs: fever, chills, myalgia, GI disturbances
- fatigue
- depression
-Neutropenia —- potentiated if given with Zidovudine
IFN-α:
- (1) is the main form of administration via (2) route
- (3) route of elimination
- (4) may accumulate
1- pegylated (attaches polyethylene glycol – improves F, given once a week)
2- IV, SQ, intralesional
3- liver and kidneys
4- theophylline
list the nucleo-side/tide analogs used in HBV therapy
lamivudine
adefovir
tenofovir
entecavir
nucleo-side/tide analogs must undergo (1) to be activated in order to inhibit (2)
they may also be converted to (3) form in order to prevent (4)
1- phosphorylation –> triphosphate form
2- inhibits HBV and HIV reverse transcription
3- monophosphate form
4- incorporated into DNA via HBV polymerase –> stops DNA synthesis
Note- suppressive. not curative
Lamivudine:
- (1) clinical uses
- prevents (2) in pregnancy, include timeline
- (3) discuss half-life in terms of (1)
- (4) discuss AEs in general
- (5) discuss resistance
1- HBV, HIV 2- vertical transmission in last 4 wks of gestation 3- intracellular half life in HBV > HIV 4- well tolerated 5- lots of resistance
Entecavir:
- (1) clinical uses
- (2) discuss half-life / dosing
- (3) discuss AEs in general
- (4) discuss resistance
1- lamivudine-resistant strains of HBV, HIV
2- prolonged –> once daily dosing
3- well-tolerated // oral F ~100%
4- rare resistance
______ has the greatest suppressive effects of the HBV nucleo-side/tide analogs
entecavir
recommended therapy for acute hepatitis
-entecavir > lamivudine / tenofovir
No PEG-IFN
recommended therapy for chronic hepatitis
- entecavir > lamivudine / tenofovir
- PEG-IFN
list the drugs for Hepatitis C infections
Non-structural protease inhibitors:
- NS3/4A inhibitors – simeprevir
- NS5A inhibitors – ledipasvir
- NS5B inhibitors – sofosbuvir
NS3/4A inhibitor = (1):
-binds (ir-/reversibly) to NS3 (3) in order to inhibit (4)
1- simeprevir
2- reversibly
3- serine protease
4- HCV replication
NS3/4A inhibitor = (1):
- used in (2) cases of HCV infections
- used in combination with (3)
- (4) AEs
1- simeprevir
2- previously untreated or failed Tx with IFN-α + ribavirin
3- ledipasvir (NS5A inhibitor)
4- Allergic rxn: severe itching, rash, photosensitivity, and rarely Steven-Johnson
NS5A inhibitor = (1):
- inhibit NS5A which is a (2) protein and is necessary for (3) viral functions
- (4) AEs
1- ledipasvir
2- phosphoprotein
3- replication, assembly, secretion
4- HA, diarrhea
NS5B inhibitor = (1):
- inhibits NS5B which is a (2) protein and is necessary for (3) viral functions
- (4) AEs
1- sofosbuvir (prodrug)
2- RNA dep. RNA poly.
3- replication –> acts as chain terminator
4- HA, fatigue
describe the main therapy for HCV
NS inhibitors (all three) IFN-α guanosine analog (entecavir)
list the drugs for herpes infections
- purine / pyrimidine analogs
- pyrophosphate analog
list the purine and pyrimidine analogs used in herpes infections
- acyclovir
- gangciclovir
- penciclovir
- cidofovir
- trifuridine
(1) is the prototype anti-herpetic agent used against (2) infections. (1) is the drug of choice for (3).
1- acyclovir
2- HSV1/2, VZV, some EBV infections —- typically HSV2 prophylaxis + immuno-compromised Pts
3- HSV encephalitis
______ is the drug of choice for HSV encephalitis
acyclovir
describe the activation of purine / pyrimidine analogs
- what is unique about CMV
- what agents is this not the case for
1) nucleoside –> monophosphate via Thymidine kinase (in virus)
2) monophosphate –> di/tri-phosphate via Host kinase
- CMV doesn’t have Thymidine kinase
- cidofovir and trifuridine don’t use Thymidine kinase
discuss mechanism of resistance in acyclovir
- altered / deficient Thymidine kinase
- altered viral DNA poly. w/ dec affinity for acyclovir
Acyclovir:
- (1) route of administration
- (2) other form
- (3) describe metabolism
1- IV, oral, topical
2- Valacyclovir – prodrug => inc oral F, less dosing
3- partially metabolized — accumulates in renal failure
list AEs for acyclovir by route of administration
Topical: local irritation
Oral: HA, n/v/d
IV: acute renal failure – obstructive crystalline nephropathy (minimized by slow infusion, prior hydration)
Gangciclovir:
- (1) route of administration
- drug of choice for (2)
- (3) AEs
1- IV, valganciclovir- prodrug for oral
2- CMV retinitis (+ CMV prophylaxis and immuno-compromised)
3- myelosuppression –> severe dose dependent neutropenia
Gangciclovir:
- (1) MOA
- (2) mechanism of resistance
1:
- phosphorylated by viral UL97 + cell kinases
- DNA poly. inhibitor + chain terminator
2:
- reduced intracellular phosphorylation
- UL97 or viral DNA poly mutations
______ is the drug of choice for CMV retinitis
gangciclovir
Cidofovir:
- (1) clinical uses
- (2) main difference in terms of MOA
- (3) route of administration
- (4) AEs + (5) combination drug
1- alternative for CMV retinitis in HIV/AIDS Pts + HSV + gangciclovir resistant HSV
2- no phosphorylation by viral kinases – only host kinases — inhibits viral DNA poly.
3- IV, topical, intravitreal (CMV retinitis)
4- Nephrotoxicity
5- probenecid – blocks tubular secretion
Penciclovir:
- active against (1) with (2) as the main clinical use
- (3) AEs
1- HSV-1/2, VZV
2- topical for HSV (cold sores) [poor oral absorption)
3- mild erythema
Trifluridine:
- active against (1)
- drug of choice for (2) (include route of administration)
1- HSV-1/2, vaccinia virus
2- HSV keratoconjunctivitis + recurrent epithelial keratitis —– ophthalmic ointment
Trifluridine:
- (1) MOA
- (2) AEs
1- triphosphate incorporated into viral DNA –> fragmentation
2- transient eye irritation, palpebral edema
______ is the drug of choice for HSV keratoconjunctivitis and recurrent epithelial keratitis
trifluridine- ophthalmic ointment
Pyrophosphate analog = (1):
-(2) is MOA and (3) is advantage compared to nucleo-side/tide analogs
1- foscarnet, phosphonoformic acid
2- selectively inhibits pyrophosphate binding site on viral DNA polymerases
3- not phosphorylation required
Foscarnet:
- effective against (1)
- (2) route of administration
- (3) AEs
1:
- CMV retinitis immunocompromised Pts
- acyclovir resistant HSV, VZV, CMV
- ganciclovir resistant CMV, VZV
2- IV
3:
- nephrotoxicity – electrolyte disturbance
- anemia
- genital ulceration in men
- hallucinations, seizures, HA in 25% Pts
