Pharmacology Chapter 49: Antivirals Page 1 of 4

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antivirals are only virustatic, they are active only against replicating viruses, not latent viruses
Agents Used to Treat HSV and VZV
acyclovir acyclic guanosine derivative mostly active against HSV-1,2, little activity against VZV
only one available for IV usage in US
required to be triphosphorylated, first phosphorylation by viral thymidine kinase, other two by host
enzymes
only active in infected cells because initial phosphorylation requires viral kinase
competes with d-GTP for DNA polymerase and results in chain termination
low bioavailability, mild CNS penetrance, shortens outbreaks by approximately 2 days
IV is TOC for HSV encephalitis, neonatal HSC, and serious HSV/VZV infection
resistance via thymidine kinase of DNA polymerase; cross-resistance with ganciclovir, valacyclovir, and famciclovir
probenecid and cimetidine clearance
zidovudine and acyclovir combination causes lethargy and somnolence
valacyclovir L-valyl ester prodrug of acyclovir with hepatic conversion on first pass
results in much higher bioavailability and CNS penetrance
TTP and HUS in HIV patients
famciclovir deacetylated via first-pass metabolism to penciclovir, an acyclic guanosine analog
requires initial phosphorylation via thymidine kinase
does not cause chain termination, but competitively inhibits DNA polymerase
polymerase affinity, but higher IC concentrations
increased bioavailability, cross-resistant with thymidine kinase
penciclovir available for topical use
docosanol inhibits fusion of cell membrane with HSV envelope, topical use for HSV
trifluridine fluorinated pyrimidine nucleoside that inhibits viral DNA synthesis in HSV, CMV, and adenovirus
phosphorylated IC via host cell enzymes
competes with thymidine triphosphate for DNA polymerase
topical for keratoconjunctivitis and recurrent epithelial keratitis due to HSV
Agents Used to Treat CMV
foscarnet and cidofovir are IV only
ganciclovir acyclic guanosine analog requiring triphosphorylation
initial phosphorylation via viral kinase UL97 in CMV infected cells
competitively inhibits DNA polymerase and causes termination of chain elongation
poor bioavailability, intraocular implant available
oral has less risk of myelosuppression compared to IV
CNS toxicity, carcinogenic and embryotoxic at high doses
increases didanosine levels when taken concurrently; probenecid and trimethoprim prolong
valganciclovir L-valyl ester prodrug, converted by esterases in intestinal wall and liver to ganciclovir
increased bioavailability; take with food
foscarnet inorganic pyrophosphate analog that inhibits HSV DNA polymerase, RNA polymerase, and HIV reverse
transcriptase directly without requiring phosphorylation
blocks pyrophosphate binding sites on above enzymes and inhibits pyrophosphate cleavage from
deoxynucleotide triphosphates
IV only often in combination with ganciclovir
used in acyclovir resistant HSV/VZV, CMV infection
resistance due to DNA polymerase, typically active against ganciclovir resistance
seizures with imipenem; anemia with zidovudine; hypocalcemia with pentamidine
saline preloading should be used to prevent nephrotoxicity
cidofovir cytosine nucleotide analog active against many viruses, IV only
must be dephosphorylated, only requires host enzymes; active against thymidine resistance
competitively inhibits DNA polymerase
CI in renal insufficiency; probenecid administration required with IV
saline administration to prevent nephrotoxicity
teratogenic; neutropenia; proteinuria, azotemia, acidosis, Fanconis syndrome
Antiretroviral Agents
combination therapy of at least three agents used to reduce viral load as much as possible
HIV-2 generally resistant to NNRTIs due to different structure of NNRTI binding pocket
NRTIs
competitive inhibition of HIV-1 reverse transcriptase and incorporation into growing DNA chain causes premature
termination due to inhibition of binding with incoming nucleotide
each agent requires cytoplasmic activation via phosphorylation to triphosphate form
possible mitochondrial toxicity due to inhibition of mitochondrial DNA polymerase gamma
hepatomegaly, lactic acidosis, hepatic steatosis, should suspend treatment in elevated AST/ALT levels
abacavir a guanosine analog with high bioavailability
combined with lamivudine (3TC), or with lamivudine and zidovudine (AZT)
test for HLA-B5701, MI risk, reduces methadone levels, n/v/d, dyspnea, fatigue
didanosine (ddI) synthetic analog of deoxyadenosine
take without food; increased with ganciclovir or tenofovir
do not administer with tenofovir

Pharmacology Chapter 49: Antivirals Page 2 of 4

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pancreatitis, especially with stavudine, zalcitabine, ribavirin, hydroxyurea

neuropathy with stavudine, isoniazid, vincristine, ribavirin
hyperuricemia; levels of ddI may increase with allopurinol; increased MI risk
emtricitabine fluorinated analog of 3TC with high bioavailability and half-life
CI in children, pregnancy, renal/hepatic failure, metronidazole, or disulfiram
given with tenofovir, helps prevent acquisition of HIV also; also with efavirenz
avoid concurrent use with 3TC
hyperpigmentation of palms and soles, especially in AA
M184V resistance, also with 3TC
lamivudine (3TC) cytosine analog often used with AZT and stavudine (d4T) or abacivir
M184V resistance, same as emtricitabine
good bioavailability, increases with TMP-SMX
avoid with zalcitabine, inhibit each others phosphorylation
stavudine (d4T) thymidine analog with excellent bioavailability
neuropathy, increased with ddI, zalcitabine, vincristine, isoniazid, or ribavirin
increased acidosis or hepatic steatosis; pancreatitis, arthralgia, AST/ALT
avoid with ddI and AZT
tenofovir acyclic nucleoside phosphonate analog of adenosine
only requires two phosphorylations; inhibits reverse transcriptase and chain termination
K65R mutation
combination with emtricitabine or efavirenz
osteomalacia, calcium and phosphate loss, proximal renal tubular toxicity
zalcitabine (ddC) cytosine analog with high bioavailability; avoid with food and antacids
neuropathy, avoid other drugs; pancreatitis
oral and esophageal ulceration
avoid with 3TC
zidovudine (AZT) deoxythymidine analog with good bioavailability and CSF penetration
renal excretion, glucuronidated in the liver
administered typically with 3TC and abacavir
reduces vertical transmission (23%)
decreases HIV-associated dementia and thrombocytopenia
myelosuppression with macrocytic anemia and neutropenia; increases with ganciclovir, ribavirin
avoid with stavudine
pregnancy
NRTIs 3TC or AZT; abacavir, ddI, emtricitabine, stavudine
NNRTI nevirapine
PIs lopinavir/ritonavir; atazanavir/ritonavir, indinavir/ritonavir, nelfinavir, ritonavir, saquinavir
nonnucleoside reverse transcriptase inhibitors (NNRTIs)
bind directly to reverse transcriptase resulting in allosteric inhibition of RNA and DNA-dependent DNA polymerase
do not compete with nucleoside triphosphates nor require phosphorylation to be active
no cross-resistance between NRTIs and NNRTIs
K103N and Y181C confer resistance across all NNRTIs
GI intolerance, rash (SJS), CYP450 metabolism (CYP3A4)
inducers nevirapine
inhibitors delavirdine
mixed inducers and inhibitors efavirenz, etravirine
delavirdine 85% bioavailable, inhibited by antacids and H 2-blockers, low CSF levels
avoid in pregnancy, SJS, erythema multiforme, AST/ALT, n/d, headache
inhibits 3A4 and 2C9
avoid with ddI, protease inhibitors
efavirenz empty stomach, given once daily
CNS effects, avoid in pregnancy, same as delavirdine
etravirine effective against other resistant drugs
inhibits both 2C9 and 2C19
avoid with some PIs and other NNRTIs
nevirapine excellent bioavailability, lipophilic with good CSF levels
peripartum administration greatly decreases vertical transmission
fulminant hepatitis with HBV, HCV coinfection
inducers will decrease it effectiveness
inhibitors will increase its levels (ketoconazole, clarithromycin, fluconazole)
protease inhibitors
prevent posttranslational cleavage of gag-pol genes into functional viral particles
do not need IC activation
Cushingoid appearance (except atazanavir), LDL and TGs, hyperglycemia, insulin resistance
saquinavir and ritonavir combination results in PR and QT prolongation
metabolized by 3A4 and strongly inhibit
atazanavir azapeptide with once daily dosing
resistance via I50L mutation

Pharmacology Chapter 49: Antivirals Page 3 of 4

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avoid with proton-pump inhibitors and other acid-reducing agents

n/v/d, headache, neuropathy, hyperbilirubinemia and jaundice
darunavir must be co-administered with ritonavir
liver and pancreatic enzymes, hepatitis
a sulfa drug, avoid in allergy
fosamprenavir prodrug of amprenavir undergoing hydrolysis in intestinal epithelium
mostly administered with ritonavir
reduced levels with high fat meals
SJS, n/v/d, perioral paresthesia
CI in children, pregnancy, renal or hepatic failure, metronidazole, or disulfiram
avoid supplemental vitamin E
give at different times than ritonavir
indinavir requires acidic environment, typically requires empty stomach
hyperbilirubinemia, nephrolithiasis (water must be ingested to avoid)
hemolytic anemia, thrombocytopenia, insomnia, n/v/d
lopinavir only with ritonavir, reduced pill burden with good compliance
ritonavir inhibits 3A4, which increases lopinavir half-life
CI with rifampin, metronidazole, disulfiram
nelfinavir diarrhea and flatulence
ritonavir high bioavailability active form after metabolism via 3A4 and 2D6
potent 3A4 inhibitor and thus increases half-life of other PIs, which is good
saquinavir and ritonavir increase QT and PR
saquinavir enhanced absorption with fatty meal
tipranavir high-fat meal increases bioavailability
avoid in head trauma or intracranial bleed, avoid combination with ritonavir
statin levels are increased causing rhabdomyolysis and myopathy
sulfa
entry inhibitors
enfuvirtide subcutaneous injection, binds to and inhibits gp41 action
maraviroc binds to CCR5, used for R5-tropic HIV-1 patients
CI in end-stage renal disease
resistance due to mutation of gp120 V3 loop
metabolized via 3A4: must increase with inducers and decrease with inhibitors
integrase strand transfer inhibitor
raltegravir pyrimidinone analog that blocks integrase preventing integration into host genome
no CYP interaction, however, should be increased if given with rifampin
avoid with antacids, metals will bind
increased CK, rhabdomyolysis, myopathy
Anti-hepatitis Agents
interferon- inhibition of viral penetration, translation, transcription, processing, maturation, and release;
increased MHC expression, increased phagocytosis
subcutaneous or IM injection; pegylated given SQ only
pegylation increases half-life and slower clearance
flu-like symptoms, increased LFTs, alopecia, myelosuppression, autoimmune exacerbation
CI in autoimmune, cardiac disease, hepatic and renal insufficiency
HBV treatment
goal is viral suppression
NRTIs 3TC, adefovir dipivoxil, tenofovir, entecavir, telbivudine, IFN-
acute exacerbation of HBV can occur if discontinued while treating HIV
adefovir dipivoxil acyclic adenine nucleotide analog
dephosphorylated via host kinases and competitively inhibits HBV DNA polymerase
reduction of carnitine, increased creatinine, lactic acidosis, hepatic steatosis, decreased phosphorous
entecavir guanosine nucleoside analog competitively inhibiting DNA polymerase
empty stomach with bioavailability of nearly 100%
superior to 3TC
lamivudine (3TC) competes with deoxycytidine triphosphate for incorporation into viral DNA
telbivudine thymidine nucleoside analog phosphorylated by host kinases to triphosphorylated form
competitively inhibits DNA and incorporates into DNA chain for termination
no interaction with CYP or food
superior to 3TC, however, resistance emerges in up 22%
myalgia, myopathy, neuropathy
tenofovir active against 3TC and entecavir resistant strains of HBV
adenosine nucleotide analog
HCV treatment
goal is viral eradication
antiviral therapy recommended after 12 weeks of IFN therapy without adequate results
ribavirin guanosine analog phosphorylated IC by host enzymes
inhibits synthesis of GTP, RNA polymerase, and RNA cap

Pharmacology Chapter 49: Antivirals Page 4 of 4

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increased availability with high-fat meals

CI in anemia, RF, vascular disease, and pregnancy, mutagenic
Anti-Influenza Agents
classification via core protein (A, B) and surface proteins (H, N)
influenza A can infect animals and undergo antigenic variation (H1N1, H1N2, H3N2)
most avian strains are resistant to amantadine and rimantadine (H5N1)
oseltamivir and zanamivir neuraminidase inhibitors, analogs of sialic acid, interfere with progeny release from
host
active against both influenza A and B
oseltamivir prodrug activated by hepatic esterases, approved for 1 year or older
zanamivir approved greater than 7years old via inhalation
amantadine and rimantadine tricyclic amines that block M2 proton ion channel of virus inhibiting its uncoating of
viral RNA preventing its replication
active against influenza A, but resistant to avian types (H1N1, H3N2)
teratogenic, anticholinergic in amantadine overdose
peramivir cyclopentane analog active against both A and B
Other Antiviral Agents
interferons IFN--2b/n3 can be used in HPV
ribavirin nebulized formulation may be used for RSV
palivizumab monoclonal antibody against A antigen on F surface protein of RSV
imiquimod topical agents for HPV warts (not in US though)