ANTIVIRAL

AGENTS
Chapter 49
Katzung
introduction
• To be effective, antiviral agents must:
• block viral entry
• active inside the host cell
• Bbock exit from the cell

• Recent research has focused on identifying agents with:

• greater selectivity
• higher potency
• in vivo stability
• reduced toxicity
introduction
• Antiviral therapy is now available for:
- herpesviruses - HCV
- HBV - papillomavirus
- influenza - HIV
- RSV

• Antivirals share the common property of being virustatic

• Options:
• Monotherapy for brief periods of time (HSV)
• Dual therapy for prolonged periods of time (HCV)
• Multiple drug therapy for indefinite periods (HIV)
AGENTS TO TREAT
HSV & VZV
ACYCLOVIR
• Structure:
• is an acyclic guanosine derivative

• MOA:
• Competes with deoxy-GTP for the viral DNA
polymerase, resulting in binding to the DNA template
as an irreversible complex
• Chain termination following incorporation into the viral
DNA

• Acyclovir requires three phosphorylation steps for

activation
ACYCLOVIR
• Clinical Use:
• Ano-genital herpes
• Herpes labialis
• Cutaneous zoster
• Post-herpetic neuralgia
• Herpes simplex encephalitis, neonatal HSV infection

• Resistance can develop through alteration in either the

viral thymidine kinase or the DNA polymerase
ACYCLOVIR
• Availability:
• Oral, intravenous and topical

• Pharmacokinetics:
• Cleared by glomerular filtration and tubular secretion
• Probenecid and cimetidine decrease acyclovir
clearance

• Side Effects:
• Nausea, diarrhea, and headache
• Reversible renal toxicity (crystalline nephropathy or
interstitial nephritis)
• Neurologic effects (tremors, delirium, seizures)
VALACYCLOVIR
• Structure:
• Valacyclovir is the L-valyl ester of acyclovir.
• Converted to acyclovir after oral administration via first-
pass enzymatic hydrolysis in the liver and intestine

• Clinical Use
• Genital herpes and varicella and zoster infections
• Orolabial herpes
• Prevents CMV disease after organ transplantation
• Prevents VZV reactivation after hematopoietic stem cell
transplantation
VALACYCLOVIR
• Pharmacokinetics:
• Oral bioavailability is 54–70%

• Side Effects:
• Nausea, headache, vomiting, or rash may occur
• Confusion, hallucinations, and seizures have been
reported
• In AIDS patients:
• Increased gastrointestinal intolerance
• Thrombotic thrombocytopenic purpura/hemolytic-
uremic syndrome
FAMCICLOVIR
• Structure:
• Diacetyl ester prodrug of 6-deoxypenciclovir, an acyclic
guanosine analog, rapidly deacetylated and oxidized
by first-pass metabolism to penciclovir

• MOA:
• Competitively inhibits the viral DNA polymerase to block
DNA synthesis

• Activation by phosphorylation is catalyzed by the virus-

specified thymidine kinase in infected cells
FAMCICLOVIR
• Clinical Uses:
• Genital herpes
• Herpes labialis

• Pharmacokinetics:
• Bioavailability is 70%
• Excreted primarily in the urine.

• Side Effects:
• Headache, nausea, or diarrhea
• Testicular toxicity in animals
AGENTS TO TREAT
CMV
GANCICLOVIR
• Structure:
• An acyclic guanosine analog

• MOA:
• Competitively inhibits viral DNA polymerase and causes
termination of viral DNA elongation

• Initial phosphorylation is catalyzed by the virus-specified

protein kinase phosphotransferase UL97 in CMV-
infected cells
GANCICLOVIR
• Pharmacokinetics:
• Activity against CMV is up to 100 times greater than
that of acyclovir
• Oral bioavailability is poor
• Clearance is linearly related to creatinine clearance
• Levels may rise with probenecid or trimethoprim
• Concurrent use with didanosine may result in increased
levels of didanosine
GANCICLOVIR
• Clinical Uses:
• Delay progression of CMV retinitis (more effective with
foscarnet in AIDS)
• CMV colitis and esophagitis
• Pneumonitis (in combination with IV cytomegalovirus Ig)
• Reduces:
• Risk of CMV infection in transplant recipients
• Hearing loss in infants with symptomatic congenital
neurologic CMV
• Risk of Kaposi’s sarcoma in AIDS
GANCICLOVIR
• Resistance
• Mutation in UL97 = decreased levels of the
triphosphorylated form of ganciclovir
• UL54 mutation in DNA polymerase = higher levels of
resistance and potential cross-resistance with
cidofovir and foscarnet

• Side Effects:
• Myelosuppression (additive w/ zidovudine, azathioprine,
or mycophenolate mofetil)
• Nausea, diarrhea, fever, rash, HA, periph neuropathy
• CNS and liver toxicity are rare
• Vitreous hemorrhage and retinal detachment
VALGANCICLOVIR
• Is an L-valyl ester prodrug of ganciclovir

• After oral administration, hydrolyzed to ganciclovir by

esterases in the intestinal wall and liver, oral
bioavailability is 60%

• Elimination is renal, through glomerular filtration and

active tubular secretion

• For CMV retinitis, prevention of CMV disease in high-risk

solid organ and bone marrow transplant recipients

• Adverse effects, drug interactions, and resistance patterns

are the same as those associated with ganciclovir
FOSCARNET
• Structure:
• Phosphonoformic acid is an inorganic pyrophosphate
analog

• MOA:
• Inhibits herpesvirus DNA polymerase, RNA polymerase,
and HIV reverse transcriptase directly without
requiring activation by phosphorylation
• Foscarnet blocks the pyrophosphate binding site of
these enzymes and inhibits cleavage of
pyrophosphate from deoxynucleotide triphosphates
FOSCARNET
• Clinical Uses:
• End-organ CMV disease (retinitis, colitis, esophagitis)
• Ganciclovir-resistant disease; acyclovir-resistant HSV
and VZV infections
• Synergistic with ganciclovir against CMV and has been
shown to be superior to either agent alone

• Pharmacokinetics:
• Available in an intravenous formulation only
• Clearance is primarily renal and is directly proportional
to creatinine clearance
FOSCARNET
• Resistance is due to point mutations in the DNA
polymerase gene

• Adverse Effects:
• Renal impairment, CNS toxicity
• Hypo- or hypercalcemia, hypo- or hyperphosphatemia,
hypokalemia, and hypomagnesemia
• Anemia
• Genital ulcerations may be due to high levels of ionized
drug in the urine
CIDOFOVIR
• Structure:
• A cytosine nucleotide analog

• MOA:
• A potent inhibitor of and as an alternative substrate for
viral DNA polymerase, competitively inhibiting DNA
synthesis and becoming incorporated into the viral
DNA chain

• Phosphorylation to the active diphosphate is independent

of viral enzymes
CIDOFOVIR
• Pharmacokinetics:
• Cidofovir phosphocholine, has a half-life of at least 87
hours and may serve as an intracellular reservoir
• Elimination is by active renal tubular secretion
• Must be administered with probenecid which blocks
active tubular secretion & decreases nephrotoxicity

• Clinical Uses:
• CMV retinitis (direct intravitreal administration is not
recommended)
• Experimentally to treat adenovirus, human
papillomavirus, BK polyomavirus, vaccinia, and
poxvirus infections
CIDOFOVIR
• Adverse effect
• Dose-dependent proximal tubular nephrotoxicity
• Proteinuria, azotemia, metabolic acidosis, and
Fanconi’s syndrome may occur
• Uveitis, ocular hypotony, and neutropenia
ANTIRETROVIRAL
AGENTS
ANTIRETROVIRAL AGENTS
• Six classes are currently available for use:
• Nucleoside/nucleotide reverse transcriptase inhibitors
(NRTIs)
• Non-nucleoside reverse transcriptase inhibitors
(NNRTIs)
• Protease inhibitors (PIs)
• Fusion inhibitors
• CCR5 co-receptor antagonists (entry inhibitors)
• HIV integrase strand transfer inhibitors (INSTIs)
Life cycle
of HIV
NRTIs
• Backbone antiretroviral therapy

• MOA:
• Act by competitive inhibition of HIV-1 reverse
transcriptase
• Incorporation into the growing viral DNA chain causes
premature chain termination due to inhibition of
binding with the incoming nucleotide
• Each agent requires intracytoplasmic activation via
phosphorylation by cellular enzymes to the
triphosphate form
NRTIs
• Resistance:
• Typical resistance mutations include:
• M184V, L74V, D67N, and M41L
• M184V mutation:
• Lamivudine or emtricitabine
• Abacavir, didanosine, and zalcitabine,
• K65R/N mutation:
• Tenofovir, abacavir, lamivudine, and emtricitabine
NRTIs
• Adverse Effects:
• Associated with mitochondrial toxicity
• Lactic acidosis with hepatic steatosis may occur (fatal)
• Dyslipidemia and insulin resistance (thymidine analogs)
• Increased risk of myocardial infarction
NRTIs
• Guanosine Analog:
• ABACAVIR

• Adnosine Analog:
• DIDANOSINE (deoxy)
• TENOFOVIR (acyclic necleoside phosphonate)

• Cytosine Analog:
• LAMIVUDINE
• EMTRICITABINE (Fluorinated)

• Thymidine Analog:
• STAVUDINE
• ZIDOVUDINE (deoxy)
NNRTIs
• MOA:
• Binds directly to HIV-1 reverse transcriptase, resulting in
allosteric inhibition of RNA- and DNA-dependent
DNA polymerase activity
• Neither compete with nucleoside triphosphates nor
require phosphorylation to be active.

• Resistance:
• K103N and Y181C mutations confer resistance to the
first-generation NNRTIs
• L100I, Y188C, G190A) confer cross-resistance
• No cross-resistance between the NNRTIs and NRTIs
NNRTIs
• Side Effects:
• Varying levels of gastrointestinal intolerance
• Skin rash, which may infrequently be serious (SJS)

• Interactions:
• Metabolize by the CYP450 system, leading to
innumerable potential drug-drug interactions
• All are substrates for CYP3A4 and can act as:
• Inducers - nevirapine
• Inhibitors - delavirdine
• Mixed inducers and inhibitors – efavirenz, etravirine
NNRTIs
• DELAVIRDINE
• EFAVIRENZ
• ETRAVIRINE
• NEVIRAPINE
• RILPIVIRINE
PIs
• MOA:
• Inhibits the HIV protease which is responsible for
cleaving these precursor molecules to produce the
final structural proteins of the mature virion core
• By preventing functional conformations, these results in
the production of immature, noninfectious viral
particles
• Do not need intracellular activation

• Resistance:
• Most common mutations are substitutions at the 10, 46,
54, 82, 84, and 90 codons
• I50L substitution during atazanavir therapy has been
assoc with increased susceptibility to other PIs
PIs
• Side Effects:
• Mild-to-moderate nausea, diarrhea
• Dyslipidemia (elevated triglyceride and LDL levels)
• A syndrome of redistribution and accumulation of body
fat:
• Central obesity
• Dorsocervical fat enlargement (buffalo hump)
• Peripheral and facial wasting
• Breast enlargement
• Cushingoid appearance
• Hyperglycemia and insulin resistance
• cardiac conduction abnormalities, including PR or QT
interval prolongation
PIs
• Less common side effects:
• Drug-induced hepatitis and rare severe hepatotoxicity
• Bone loss and osteoporosis after long-term use is under
investigation
• Increased spontaneous bleeding in patients with
hemophilia A or B
PIs
• Interactions:
• Extensively metabolized by CYP3A4
• Amprenavir and ritonavir, are also inducers of specific
CYP isoforms
• Ritonavir acts as a pharmacokinetic enhancer rather
than an antiretroviral agent by its potent CYP3A4
inhibitory properties
PIs
• ATAZANAVIR
• DARUNAVIR
• FOSAMPRENAVIR
• INDINAVIR
• LOPINAVIR
• NELFINAVIR
• RITONAVIR
• SAQUINAVIR
• TIPRANAVIR
Entry Inhibitors
• Viral attachment to the host cell entails binding of the viral
envelope glycoprotein complex gp160 (consisting of
gp120 and gp41) to its cellular receptor CD4
• This binding induces conformational changes in gp120
that enable access to the chemokine receptors
CCR5 or CXCR4
• Conformational changes in gp120, allows exposure to
gp41 and leads to fusion of the viral envelope with
the host cell membrane with subsequent entry of the
viral core into the cellular cytoplasm
Entry Inhibitors
• Enfuvirtide
• Synthetic 36-amino-acid peptide fusion inhibitor

• MOA:
• Binds to the gp41 subunit of the viral envelope
glycoprotein, preventing the conformational changes
required for the fusion of the viral and cellular
membranes

• Is the only parenterally administered antiretroviral agent

• Metabolism appears to be by proteolytic hydrolysis

without involvement of the CYP450 system
Entry Inhibitors
• Enfuvirtide
• Resistance can result from mutations in gp41

• Adverse effects:
• Local injection site reactions, consisting of painful
erythematous nodules
• Other side effects may include insomnia, headache,
dizziness, and nausea
• Eosinophilia is the primary laboratory abnormality
Entry Inhibitors
• Maraviroc
• Binds specifically and selectively to the host protein
CCR5, one of two chemokine receptors necessary
for entrance of HIV into CD4+ cells
• Resistance is associated with one or more mutations in
the V3 loop of gp120
• No cross-resistance with drugs from any other class,
Entry Inhibitors
• Maraviroc
• Adverse effects of include cough, upper respiratory tract
infections
• Muscle and joint pain, diarrhea, sleep disturbance
• Elevations in serum aminotransferases, hepatotoxicity
preceded by a systemic allergic reaction (ie, pruritic
rash, eosinophilia, or elevated IgE)
• Myocardial ischemia and infarction
INSTIs
• MOA:
• Binds integrase, an essential viral enzyme
• Inhibits strand transfer, the third and final step of
provirus integration, thus interfering with the
integration of reverse-transcribed HIV DNA into the
chromosomes of host cells

• Side Effects:
• Headache and gastrointestinal effects
• Nervous system (including neuropsychiatric)
• Rare and severe events include systemic
hypersensitivity reactions and rhabdomyolysis
INSTIs
• DOLUTEGRAVIR
• ELVITEGRAVIR
• RALTEGRAVIR
AGENTS TO TREAT
HEPATITIS B VIRUS
Anti-HBV
• The goals of chronic HBV therapy are:
• Suppression of HBV DNA to undetectable levels
• Seroconversion of HBeAg (or more rarely, HBsAg) from
positive to negative
• Reduction in elevated hepatic transaminase levels

• Treatment leads to:

• Improvement in necroinflammatory disease
• Decreased risk of hepatocellular carcinoma and
cirrhosis
• Decreased need for liver transplantation
Anti-HBV
• Current therapies suppress HBV replication without
eradicating the virus, viral DNA exists in stable form
serving as a reservoir for HBV throughout the life of
the cell and resulting in the capacity to reactivate

• Oral nucleoside/nucleotide analogs

• Lamivudine, adefovir dipivoxil, tenofovir, entecavir,
Telbivudine
• Injectable interferon drugs
• Interferon alfa-2b, pegylated interferon alfa-2a
Anti-HBV
• ADEFOVIR DIPIVOXIL
• Competitively inhibits HBV DNA polymerase and
causes chain termination after incorporation into
viral DNA

• ENTECAVIR
• Competitively inhibits all three functions of HBV DNA
polymerase, including base priming, reverse
transcription of the negative strand, and synthesis of
the positive strand of HBV DNA
Anti-HBV
• LAMIVUDINE
• Inhibits HBV DNA polymerase

• TELBIVUDINE
• Competitively inhibits HBV DNA polymerase, resulting
in incorporation into viral DNA and chain termination

• TENOFOVIR
• analog of adenosine
AGENTS TO TREAT
HEPATITIS C VIRUS
Anti-HCV
• Primary goal of treatment in patients with HCV infection is
viral eradication

• Achievement of sustained viral response (SVR), defined

as the absence of detectable viremia 24 weeks after
completion of therapy

• SVR is associated with improvement:

• Liver histology
• Reduction in risk of hepatocellular carcinoma
• Regression of cirrhosis as well
Anti-HCV
• POLYMERASE INHIBITORS
• Sofosbuvir
• Inhibits HCV NS5B RNA-dependent RNA polymerase

• PROTEASE INHIBITORS
• Boceprevir, simeprevir, and telaprevir
• Inhibit HCV replication directly by binding to the NS3/4A
protease that cleaves HCV-encoded polyproteins

• RIBAVIRIN
• Interfere with the synthesis of guanosine triphosphate,
to inhibit capping of viral messenger RNA, and to inhibit
the viral RNA-dependent polymerase
ANTI-INFLUENZA
AGENTS
Anti-influenza Agents
• Influenza virus strains are classified by:
• Core proteins (ie, A, B, or C)
• Species of origin (eg, avian, swine)
• Geographic site of isolation.

• Influenza A, the only strain that causes pandemics, is

classified into 16 H (hemagglutinin) and 9 N
(neuraminidase)
OSELTAMIVIR & ZANAMIVIR
• MOA:
• Competitively and reversibly interact with the active
enzyme site to inhibit viral neuraminidase activity at
low nanomolar concentrations, resulting in clumping
of newly released influenza virions to each other and
to the membrane of the infected cell

• Interfere with release of progeny influenza virus from

infected host cells, thus halting the spread of
infection within the respiratory tract
OSELTAMIVIR & ZANAMIVIR
• Oseltamivir:
• Orally administered prodrug that is activated by hepatic
esterases
• Oral bioavailability is approximately 80%
• Excretion is by glomerular filtration & tubular secretion
• Probenecid reduces its renal clearance by 50%
• Adverse effects:
• Nausea, vomiting, and headache
• Fatigue and diarrhea
• Rash is rare
• Neuropsychiatric events (self-injury or delirium)
OSELTAMIVIR & ZANAMIVIR
• Zanamivir
• Administered directly to the respiratory tract via
inhalation
• Potential adverse effects include cough, bronchospasm
(occasionally severe), reversible decrease in
pulmonary function, and transient nasal and throat
discomfort
• Is not recommended for patients with underlying airway
disease
AMANTADINE & RIMANTADINE
• MOA:
• Blocks the M2 proton ion channel of the virus particle
and inhibit uncoating of the viral RNA within infected
host cells, thus preventing its replication
• Active against influenza A only

• Amantadine is excreted unchanged in the urine

• Rimantadine undergoes extensive metabolism by

hydroxylation, conjugation, and glucuronidation
before urinary excretion
AMANTADINE & RIMANTADINE
• Adverse effects:
• Gastrointestinal (nausea, anorexia)
• Central nervous system (nervousness, difficulty in
concentrating, insomnia, light-headedness)
• Marked behavioral changes, delirium, hallucinations,
agitation, and seizures)
• Less frequent with rimantadine than with amantadine
• Associated with high plasma concentrations
• Risk factors are:
• Renal insufficiency, seizure disorders, or advanced
age; concomitant antihistamines, anticholinergic
drugs, hydrochlorothiazide, and trimethoprim-
sulfamethoxazole
THANK YOU