HSV Flashcards
Acyclovir activation
PRODRUG
Structure: acyclic guanosine lacking 3’OH
Acyclovir–>viral thymidine kinase–>acyclovir-MP–>cellular GMP kinase–>acyclovir-DP–>cellular kinase–>acyclovir-TP (active form)
With viral thymidine kinase located in virus, allows it to selectively accumulate in infected cells after phosphorylation (trapped)
Acyclovir MOA
Acyclovir-TP competitively inhibits viral DNA polymerase by competing with endogenous dGTP to inhibit viral replication
Acyclovir-TP is incorporated into the DNA acting as an immediate chain-terminator with lack of 3’OH
Acyclovir spectrum
HSV-1, HSV-2, VZV
Acyclovir PK
Oral bioavailability is 10-20%
Not affected by food
Renally eliminated by glomerular filtration and tubular secretion
- renally dose adjusted
- removed by HD (10%/hr)
Dose adjust in obesity (adj BW)
Acyclovir Side effects
Nephrotoxicity–>IV
- reversible increase in BUN and SCr
- Add fluids when administering
Neurotoxicity–>reversible
Thrombophlebitis–>IV
Headache–>oral only
Acyclovir Resistance
Mutation in viral thymidine kinase (most common)
Mutation in viral DNA polymerase
Valacyclovir activation
PRODRUG
Structure: L-valyl ester of acyclovir
Valacyclovir–>dipeptide transporter–>intestinal + hepatic esterase–>acyclovir–>acyclovir-TP
Valacyclovir MOA
Acyclovir-TP competitively inhibits viral DNA polymerase by competing with endogenous dGTP to inhibit viral replication
Acyclovir-TP is incorporated into DNA acting as an immediate chain-terminator with lack of 3’OH
Valacyclovir PK
Oral bioavailability is 50%
Not affected by food
Renally eliminated by glomerular filtration and tubular secretion
- renally dose adjusted
- removed by HD
Famciclovir Activation
PRODRUG
1st pass metabolism
Famciclovir–>esterase (removes 1 ester)–>intermediate–>esterase (removes 1 ester–>intermediate–>oxidase (adds carbonyl)–>penciclovir–>viral and cellular kinase–>penciclovir-TP
Famciclovir MOA
Penciclovir-TP competitively inhibits viral DNA polymerase by competing with endogenous dGTP to inhibit viral replication
Penciclovir-TP does NOT cause immediate chain termination–>allows for short chain elongation due to 3’OH
Famciclovir spectrum
Acute herpes zoster
Primary and recurrent HSV-2
Penciclovir spectrum
Recurrent herpes labialis
Famciclovir PK
Oral bioavailability as famciclovir is 70%
Linear kinetics: concentration increases proportional to drug given
Renally excreted by glomerular filtration and tubular secretion (90%)
- renally dose adjusted
Famciclovir drug interaction
Probenecid–>decreases renal clearance
Famciclovir cross-resistance
Viral kinase mutation confer cross-resistance to penciclovir and acyclovir
Ganciclovir
PRODRUG
Ganciclovir MOA
Ganciclovir-TP competitively inhibits viral DNA polymerase by competing with endogenous dGTP to inhibit viral replication
Ganciclovir-TP does NOT cause immediate chain termination–>allows for short chain elongation due to 3’OH
Ganciclovir spectrum
CMV retinitis–>IV,IO,PO
CMV prophylaxis–>PO
Ganciclovir PK
Oral bioavailability is 6-9%
- take with food to increase absorption
T1/2=12-24 hours
Renally eliminated by glomerular filtration and tubular secretion (90%)
- renally dose adjusted
- HD removes 50%
Ganciclovir side effects
Bone marrow suppression
-reversible
-neutropenia (40%), thrombocytopenia (20%)
- monitor CBC: stop if ANC < 500/mm3 or platelet < 25,000/mm3
Phlebitis
Ganciclovir resistance
Mutations in CMV kinase (UL97 gene)
- No cross-resistance with cidofovir or foscarnet
Mutations in CMV DNA polymerase (UL54)
- Cross-resistance with cidofovir or foscarnet
Valganciclovir
PRODRUG
Structure: monovalyl ester of ganciclovir
Rapidly converted to ganciclovir by intestinal and hepatic esterases
Valganciclovir MOA
Ganciclovir-TP competitively inhibits viral DNA polymerase by competing with endogenous dGTP to inhibit viral replication
Ganciclovir-TP does NOT cause immediate chain termination–>allows for short chain elongation due to 3’OH
Valganciclovir spectrum
CMV retinitis (AIDS patients)
Valganciclovir PK
Oral bioavailability is 60%
- take with food to increase AUC by 30%
Renally eliminated by glomerular filtration and tubular secretion
- renally dose adjusted
- HD removes 50%
Foscarnet structure
inorganic pyrophosphate (phosphonoformic acid)
Foscarnet MOA
Carboxyl overlaps with binding site of B-phosphate and phosphonates occupy position of y-phosphate–>blocks pyrophosphate binding site of viral DNA polymerase–>inhibits cleavage of pyrophosphate from dNTPs–>traps polymerase in closed formation
DOES NOT REQUIRE PHOSPHORYLATION
Foscarnet spectrum
Last line for CMV retinitis
- dose adjusted based on renal function
- synergy with ganciclovir for CMV
Foscarnet PK
Poor oral bioavailability–>IV only
- up to 30% may be deposited into bone due to phosphate
Moderate CNS concentration (13-68%)
Renally eliminated unchanged via glomerular filtration
- renally dose adjusted
- HD removes 50%
Foscarnet SE
Nephrotoxicity–>dose limiting
Hydrate with 0.75-1 L of NS or D5W prior to first infusion
- hydrate 0.75-1 L for 90-120 mg/kg after
- hydrate 0.5 L for 40-60 mg/kg after
Hypocalcemia
Hypokalemia
Hypomagnesemia
Hypo/hyperphosphatemia
Headaches
Foscarnet drug interactions
nephrotoxic drugs, pentamidine
Foscarnet resistance
Mutation in viral DNA polymerase
Mutation in HIV RT
Cross-resistance in ganciclovir for CMV isolates
Cidofivir activation
acyclic nucleoside phosphonate analog of cytosine
phosphonate cannot be cleaved by cellular esterases–>stable
Cidofivir-MP (native form)–>cellular kinase–>cidofivir-DP–>cellular kinase–>cidofivir-TP (active
Cidofivir MOA
Cidofivir-TP competitively inhibits viral DNA polymerase by competing with endogenous dGTP to inhibit viral replication
Cidofivir-TP is incorporated into DNA acting as a chain-terminator
- requires two consecutive incorporations
Poor substrate for cellular (human) DNA polymerase but higher selective for viral DNA polymerase
Cidofivir spectrum
HSV-1, HSV-2, VZV, CMV
CMV retinitis (IV)
Cidofivir PK
Long intracellular t1/2 life=17-65 h
Phosphocholine metabolite can serve as intracellular reservoir of 87 hours
Cidofivir side effects
nephrotoxicity–>dose-limiting
Penciclovir vs Acyclovir
Penciclovir> acyclovir for affinity to HSV thymidine kinase
- levels of penciclovir-TP are higher than acyclovir-TP in infected cells
Penciclovir-TP> acyclovir-TP for stability in HSV infected cells
- t1/2 is much longer
Acyclovir-TP>penciclovir-TP for viral DNA polymerase
Net: similar efficacy
