antiviral agents Flashcards
(52 cards)
acyclovir MOA
Conversion to active form – acyclovir triphosphate
-Viral thymidine kinase** in herpes simplex virus (HSV) and varicella zoster virus (VZV) converts acyclovir to acyclovir monophosphate
-Human cellular kinases convert acyclovir monophosphate to acyclovir diphosphate and then to acyclovir triphosphate (active form)
MOA – inhibition of viral DNA replication
-Acyclovir-TP competitively inhibits viral DNA polymerase → inhibition of viral replication
-Acyclovir-TP is incorporated into viral DNA → premature chain termination
Mechanisms of resistance in HSV and VZV
-Absence (TK-deficient) or partial or altered production of viral thymidine kinase (most common)
-Altered viral DNA polymerase
acyclovir SOA
Herpes simplex virus (HSV) types 1 and 2
Varicella zoster virus (VZV)
Order of activity: HSV-1 > HSV-2 > VZV > EBV»_space; CMV
acyclovir PKs
Absorption
-Oral bioavailability ≈ 10-20% (not affected by food)
-Dose-dependent oral absorption (bioavailability decreases with increasing dose)
Distribution
-Widely distributed in tissues and body fluids – correlates with total body H2O
-around 50% of IV acycovir penetrates the CSF**
-9-33% protein bound (15% average)
Metabolism/Elimination
-Eliminated renally by glomerular filtration and tubular secretion (probenecid increases the half-life and AUC)
-62-91% of IV dose excreted unchanged in urine (14% after PO)
-Half-life ≈ 2.5-3.5 hours (19.5 hours in anuria) → adjust for renal dysfunction
-Removed by hemodialysis – ≈ 60% during 6 hour session (10% per hour); administer dose after dialysis
-Peritoneal dialysis – no effect on acyclovir pharmacokinetics
acyclovir and HSV
Primary genital HSV: 400 mg PO TID or 200 mg PO q4h (5x/day) for 7-10 days
Recurrent genital HSV: 400 mg PO TID for 5 days
Chronic suppression of genital HSV: 400 mg PO BID for 5 days; 800 mg PO BID for 5 days; 800 mg TID for 2 days
HSV encephalitis: 10 mg/kg IV q8h for 10 days
Mucocutaneous disease in immunocompromised host: 5 mg/kg IV q8h or 400 mg PO TID for 7 days
Neonatal HSV 45-60 mg/kg/day IV q8h for 14-21 days
acyclovir and VZV
VZV (shingles): 800 mg PO q4h (5x/day) for 7-10 days
Severe VZV in immunocompromised host: 10 mg/kg IV q8h for 7 days
Adult with chicken pox: 800 mg 4x/day for 5 days
acyclovir and prevention of HSV and CMV disease in transplant patients
HSV seropositive bone marrow transplant patients: 125-250 mg/m2 IV q8h, then 400 mg PO 5x/day (begin 6 hours before transplant; continue for 6 weeks)
CMV seropositive bone marrow transplant patients: 10 mg/kg IV q8h
acyclovir dosing
must be dose adjusted
NOT LINEAR
dosing in obesity - recommended adult dose based on IBW
acyclovir AEs
Nausea, vomiting, diarrhea, rash, and headache with oral acyclovir
Nephrotoxicity (crystalline nephropathy)
-Reversible increase serum creatinine and BUN in 5-10% of patients
-Risk factors: bolus infusion (need to administer over 1 hour), dehydration (maintain adequate hydration), preexisting renal insufficiency, high acyclovir concentrations (> 25 µg/ml)
Neurotoxicity - reversible
-Lethargy, confusion, agitation, disorientation, hallucination, seizures, coma
-Majority of cases – severe renal insufficiency
Thrombophlebitis with IV form (alkaline pH ≈ 11)
Thrombotic thrombocytopenic purpura/hemolytic uremic syndrome (TTP/HUS) –
reported in immunocompromised patients
acyclovir availability
Oral -Tablets – 400 mg, 800 mg -Capsule – 200 mg -Suspension – 200 mg per 5 mL Intravenous – 500 mg and 1 g vials (rapid or bolus IV infusion and IM/SQ injection must be avoided)
valacyclovir MOA
L-valyl ester prodrug of acyclovir – same MOA as acyclovir
valacyclovir SOA
same as acyclovir
valacyclovir PKs
Rapidly absorbed and completely converted to acyclovir by intestinal and hepatic metabolism following oral administration – peak concentrations achieved in 1-3 hours
Relative bioavailability of acyclovir is 3-5 times greater with valacyclovir (55%)
May be given without regards to meals
Removed by hemodialysis (dose after dialysis)
clinical indications
Cold sores (herpes labialis): 2 g q12h for 1 day (begin at earliest symptom onset)
Varicella zoster virus (preferred over PO acyclovir): 1 gram PO q8h for 7 days (start within 48-72 hours of rash onset)
Primary genital HSV: 1 gram PO BID for 7-10 days
Recurrent genital HSV: 500 mg PO BID for 3 days or 1 g daily for 5 days
Suppression of genital HSV: 500-1,000 mg PO once a day in immunocompetent patients (1 gram if ≥ 10 outbreaks/year); 500 mg PO BID in HIV-infected patients
Adjust for renal dysfunction
valacyclovir AEs
Same as oral acyclovir – headache, nausea, diarrhea, abdominal pain, dizziness, CNS
Thrombotic thrombocytopenic purpura/Hemolytic uremic syndrome (TTP/HUS) reported with high doses (8 grams/day) in immunocompromised patients
famciclovir structure/chem/MOA
Diacetyl ester prodrug of penciclovir (nucleoside analog similar to acyclovir)
Oral famciclovir undergoes rapid and extensive conversion to penciclovir
Penciclovir is phosphorylated by viral thymidine kinase to penciclovir monophosphate and eventually to penciclovir triphosphate by cellular enzymes → inhibits viral replication
Penciclovir triphosphate is ≈ 100-fold less potent than acyclovir triphosphate in inhibiting viral DNA polymerase (present in higher concentrations)
famciclovir SOA
HSV-1, HSV-2, and VZV
famciclovir PKs
Well absorbed orally (penciclovir F ≈ 77% when given as famciclovir) Penciclovir concentrations increase in proportion to famciclovir dose (linear) Food slows absorption, decreases Cmax by 50% – no significant effect on overall AUC of penciclovir (dose may be administered without regards to food) Extensive distribution (Vdβ 1.1 L/kg); less than 20% protein binding Plasma half-life of penciclovir ≈ 2.5 hours (intracellular half-life 7-20 hours) ≈ 90% of penciclovir is excreted unchanged in urine by tubular secretion and glomerular filtration Dose reduction is recommended in renal dysfunction No effect of mild to moderate hepatic impairment on penciclovir AUC – no dosage adjustment needed
famciclovir clinical indications
Cold sores (herpes labialis): 1.5 g single dose (at symptom onset)
Primary genital HSV: 250 mg PO TID for 7-10 days
Recurrent genital HSV: 125 mg PO BID for 5 days; 1 g PO BID for 1 day; 500 mg PO x 1, then 250 mg PO BID for 2 days
Suppression of genital HSV: 250 mg PO BID
VZV: 500 mg PO TID for 7 days (begin within 72 hours of rash onset)
HIV-infected patients (recurrent orolabial or genital herpes): 500 mg PO BID for 7 days
famciclovir AEs
Generally well tolerated
Headache, nausea, vomiting, diarrhea
Acute renal failure – in patients with underlying renal disease receiving higher than recommended dosing for renal insufficiency
famciclovir DIs
probenecid decreases renal clearance, increases serum concentrations
famciclovir availability
125 mg, 250 mg, 500 mg tablets
ganciclovir SOA
HSV-1, HSV-2
VZV
Cytomegalovirus (CMV)**
Epstein-Barr virus (EBV)
ganciclovir MOA
In cells infected with HSV or VZV, monophosphorylation by viral thymidine kinase → diphosphorylation → triphosphorylation (active form)
In CMV-infected cells, ganciclovir is mono-phosphorylated by a CMV-encoded protein kinase (UL97 gene), then to the di- and triphosphate forms by cellular kinases
GCV triphosphate inhibits viral DNA polymerase and/or incorporation into viral DNA → inhibits viral replication
Resistance – UL97 gene mutation which leads to viral kinase deficiency or altered viral DNA polymerase
ganciclovir PKs
Low oral bioavailability ≈ 5% (up to 9% with food) and protein binding (1-2%)
Concentrations following IV administration
-Aqueous humor and sub-retinal fluid – similar to plasma concentrations
-CSF – 24-70% of plasma
-Brain tissue – 40% of plasma
Plasma half-life ≈ 3.5 hours (intracellular half-life >24 hours)
> 90% eliminated unchanged by glomerular filtration and tubular secretion
Half-life increases as renal function decreases – adjust dose for renal dysfunction
Hemodialysis removes ≈ 50%
