ANTI-VIRAL AGENTS

DR. NJAU.N.N.

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 INTRODUCTION
• Viruses are obligate intracellular parasites.

• REPLICATION depends on the synthetic processes

of the host cell.

• Therefore, antiviral agents must either BLOCK

1. entry into the cell or
2. be active inside the host cell to be
effective.
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• Viral replication peaks at or before the
manifestation of clinical symptoms.

• Optimal efficacy of antiviral agents depends on;

1. early initiation therapy or
2. prevention of infection.

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Viral replication involves:
1. Adsorption and penetration into susceptible
host cells

2. Uncoating of viral nucleic acid

3. Synthesis of early, regulatory proteins e.g.

Nucleic acid polymerases
4
4. Synthesis of RNA or DNA

5. Synthesis of late, structural proteins

6. Assembly (maturation) of viral particles

7. Release from the cell

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 Classification
1. Agents used to treat Herpes Simplex Virus (HSV)
and Varicella Zoster Virus (VZV)
• Acyclovir
• Valacyclovir
• Famciclovir
• Forscanet
• Penciclovir - topical
• Docosanol - “
• Trifluridine - “
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2. Agents used in the treatment of
Cytomegalovirus (CMV)
• Valganciclovir
• Ganciclovir
• Cidofovir
• Forscanet

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3. Anti-influenza agents
• Amantadine
• Rimantadine
• Zanamivir
• Ostelamivir

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4. Anti-hepatitis agents (specifically hepatitis B
virus (HBV))
• Lamivudine
• Adefovir
• Entecavir
• Interferon alpha
• Ribavirin

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 ANTI-HERPES AGENTS
1. Acyclovir
• It mainly has clinical activity against HSV 1 and
2 and against VZV.

• Weaker activity against Ebstein Barr Virus

(EBV), CMV HSV 6.

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 Mechanism of action
• Requires 3 phosphorylation steps for activation.

• 1st to be converted to the monophosphate derivative

by the virus-specified thymidine kinase and then to the
di- and tri-phosphate compound by the host cell’s
enzymes.

• The viral kinase is required for the first

phosphorylation. Acyclovir is selectively activated and
the triphosphate accumulates only in infected cells.
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• Acyclovir triphosphate inhibits viral DNA
synthesis by two mechanisms:

1. Competitive inhibition of dGTP for the viral

DNA polymerase, with

2. binding to the DNA template as an irreversible

complex and chain termination following
incorporation into the viral DNA.
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 Resistance
• Resistance to acyclovir can develop in HSV or
VZV through ALTERATION in either
• the viral thymidine kinase or
• viral DNA polymerase.

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 Pharmacokinetics
• Acyclovir is available in oral, IV and topical
formulations.

• Bioavailability of the oral formulation is 15-

20%.

• Cleared primarily by glomerular filtration and

tubular secretion.
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• T ½ is 3-4 hours in patients with normal renal
function and 20 hours in patients with anuria.

• Anuric patients give 1/6 of the normal

therapeutic dose.

• Readily cleared by haemodialysis but not

peritoneal dialysis.
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 Clinical uses
1. Primary herpes infections

2. Recurrent infections of genital and labial herpes

3. HSV proctitis

4. Herpes encephalitis and neonatal HSV infection

NB: VZV is less susceptible to acyclovir than HSV

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 Adverse effects
• Nausea, diarrhoea, headache

• IV- renal insufficiency or neurologic toxicity

with tremors and delirium. Uncommon with
adequate hydration and avoidance of rapid
infusion rates.

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 2. Valacyclovir
• Is the L-valyl ester of acyclovir.

• Rapidly converted to acyclovir after oral

ingestion.

• In vitro activity, mechanism of action

(pharmacodynamics), emergence of resistance
and pharmacokinetics are identical to those of
acyclovir.
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 Clinical uses
• Used for treatment of patients with recurrent
genital herpes

• Herpes zoster infections

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 Adverse effects
• Well tolerated

• Nausea, diarrhea and headache have been

reported.

• HIV/AIDS patients receiving high doses have

an increased incidence of GI intolerance and
thrombotic microangiopathies-TTP and HUS.
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 3. Famciclovir
• It is a pro-drug

• Rapidly converted to penciclovir through 1st

pass metabolism.

• Penciclovir is the active form.

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 Mechanism of action
• Activation by phosphorylation is catalysed by
the virus-specified thymidine kinase in
infected cells followed by competitive
inhibition of the viral DNA polymerase to
inhibit DNA synthesis.

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 Pharmacokinetics
• Available orally

• Bioavailability of penciclovir is 70%

• Clearance of penciclovir and dosage

adjustments is similar as to those for
acyclovir

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 Clinical uses
• Recurrent genital herpes

• Herpes zoster infections

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 Adverse reactions
• Headache, diarrhoea and nausea though the
drug is well tolerated.

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 3a. Penciclovir
• Guanosine analog

• Active metabolite of famciclovir for active use

• 1% cream is effective for treatment of recurrent

herpes labialis in immunocompetent adults.

• Shortens healing time

• Side effects-uncommon
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 4. Docosanol
• M.O.A: It inhibits fusion between the host
cell plasma membrane and the HSV
envelope.

• Therefore, prevents viral entry into host cells

and subsequent viral replication.

• Available as topical docosanol 10% cream.

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 5. Trifluridine
• Trifluorothymidine

• Fluorinated pyrimidine nucleoside that

inhibits viral DNA synthesis in
• HSV1,
• HSV 2,
• vaccinia and
• some adenoviruses.
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• Phosphosrylated intracellularly to its active
form by host cell enzymes and then competes
with thymidine triphosphate for
incorporation by the viral DNA polymerase.

• Incorporation of trifluridine triphosphate into

both VIRAL and HOST DNA prevents its
systemic use (available for topical use only).

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 Clinical uses
• 1% solution is effective in treating
keratoconjuctivitis and recurrent epithelial
keratitis due to HSV1 and HSV 2.

• Topical application of trifluridine solution

alone or in combination with IFN α ; treatment
of acyclovir-resistant HSV infections.

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 ANTI-CMV AGENTS
1. Ganciclovir
• Guanosine analogue

• Requires triphosphorylation for activation prior

to inhibiting the viral DNA polymerase.

• Has activity against CMV, HSV, VZV, and EBV

• **100 times more active than acyclovir in the

treatment of CMV.**
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 Pharmacokinetics
• Available in IV and oral formulations

• Oral bioavailabilty is poor: 6-9%.

• T ½ is 2-4 hours with normal renal function.

• Dosage adjustment is recommended for

creatinine clearances less than 80mL/min.

• Readily cleared by dialysis. 32

 Clinical uses
• The treatment of CMV retinitis in patients
with HIV/AIDS.

• Also used to reduce the incidence of

symptomatic CMV disease if administered
before organ transplantation .

• CMV colitis and eosphagitis.

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• Administered intraocularly to treat CMV retinitis,
either by direct intravitreal administration or via an
intraocular implant.

• The implant achieves high and prolonged intraocular

levels of ganciclovir, delays progression of retinitis to a
greater degree than systemic therapy with ganciclovir.

• Concurrent therapy with a systemic anti-CMV agent is

recommended.
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 Adverse reactions
• Myelosuppression may be additive in patients
receiving both ganciclovir, mycophenolate
mofetil and zidovudine.

• CNS toxicity; headache, changes in mental

status, seizures has been rarely reported.

• Is mitogenic in mammalian cells and

carcinogenic and embryotoxic in animals.
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 2. Valganciclovir
• L-valyl ester prodrug of ganciclovir that exists as a
mixture of two diastereomers .

• Well absorbed

• After oral administration, both diastereomers are

rapidly hydrolyzed to ganciclovir by intestinal and
hepatic esterases.

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• Bioavailability of oral valganciclovir is 60%; it is
recommended that the drug be taken with food.

• Plasma protein binding is less than 2%.

• The major route of elimination is renal—through

glomerular filtration and active tubular
secretion.

• Plasma concentrations are reduced ~ 50% by

hemodialysis.
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 Clinical use
• Indicated for the treatment of CMV retinitis in
patients with AIDS.

• Prevention of CMV disease in high-risk kidney,

heart, and kidney-pancreas transplant patients.

• Adverse effects, drug interactions, and resistance

patterns are the same as those associated with
ganciclovir.
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 3. Cidofovir
• Cytosine nucleotide analog.

• Has in vitro activity against CMV, HSV 1,2, VZV,

EBV, Adenovirus and HPV.

• Phosphorylation to the active diphosphate is

independent of virus infection

• Can be given IV, intravitreally.

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• The terminal T 1/2 is 2.6 hours but of the active
metabolite, cidofovir diphosphate, has a
prolonged intracellular half-life of 17–65 hours,
thus allowing widely spaced administration.

• A separate metabolite, cidofovir phosphocholine,

has a half-life of at least 87 hours and may serve
as an intracellular reservoir of active drug.

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• CSF penetration is poor.

• Elimination involves active renal tubular

secretion.

• High-flux hemodialysis has been shown to

reduce the serum levels of cidofovir by
approximately 75%.
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 Clinical uses
• IV cidofovir is effective for the treatment of CMV
retinitis.

• Has been used experimentally to treat adenovirus

infections.

NB: IV cidofovir must be administered with probenecid

which
1. blocks active tubular secretion and
2. decreases nephrotoxicity.
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 Adverse reactions
• Nephrotoxicity is the major dose limiting
toxicity.

• Concurrent administration with other

nephrotoxic agents eg. Amphotericin B,
aminoglycosides, NSAIDs should be avoided.

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 4. Foscarnet
• An organic pyrophosphate compound that
inhibits viral enzymes;
1. DNA polymerase,
2. RNA polymerase,
3. HIV reverse transcriptase.

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 Pharmacokinetics
• IV formulation ONLY.

• Poor oral bioavailability, and GI intolerance have

precluded the production of oral formulation.

• CSF concentrations are approximately 2/3 of

steady state serum concentrations.

• Clearance is directly proportionate to creatinine

clearance. 45
• Initial elimination t1/2 is 4-8 hours then
prolonged to 3-4 days in a patient with normal
renal function.

• Serial dose adjustments is according to the

calculated creatinine clearance throughout
the administration of the drug.

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 Clinical uses
• CMV retinitis
• CMV colitis
• CMV esophagitis
• Acyclovir resistant VZV infection

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 Adverse effects
• Renal insufficiency

• Hypo/hyper calcaemia, hyper/hypo

phosphatemia.

• Genital ulcerations due to high levels of ionized

drug in the urine

• CNS- headache, hallucinations, seizures.

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 To reduce adverse effects;
• Use of an infusion pump to control the rate is
preferred.

• Saline preloading and avoidance of other

nephrotoxic drugs!!!

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 ANTI-INFLUENZA AGENTS
• Influenza virus strains are classified by
their
1. core proteins i.e. A, B, C ;
2. species of origin- avian, swine ;
3. Geographical site of isolation.

• Influenza A is the only strain that causes

pandemics. 50
 1. Amantadine and Rimantadine
• Amantadine and its methyl derivative inhibit the uncoating
of the viral RNA within the 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 glucoronidation before
urinary excretion.
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• Dose reductions are required for both in the
elderly patients with renal insufficiency and
for rimantadine in patients with marked
hepatic insufficiency.

• Without resistance, both drugs are 70-90%

protective in the prevention of clinical illness
when initiated before exposure.

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 Adverse effects
• Nausea, anorexia

• CNS- nervousness, difficulty in concentrating,

insomnia, light headedness with Rimantadine

• Birth defects have been reported after

exposure during pregnancy.

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 2. Zanamivir and Oseltamivir
• Neuraminidase inhibitors; analogs of sialic
acid: They interfere with release of progeny
influenza virus from infected cells, to new
host cells, halting the spread of infection
within the respiratory tract.

• Both are active against both Influenza A and

B viruses.

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• Zanamivir is delivered directly to the
respiratory tract via inhalation.

• 10-20% of the active compound reaches the

lungs and the rest is deposited in the
oropharynx.

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• Oseltamivir is administered orally as a pro-drug.

• It is activated by hepatic esterases and widely

distributed throughout the body.

• Dose reduction in patients with renal insufficiency

is necessary.

• T ½ is 6-10 hours, excretion is primarily in the urine.

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 Adverse effects
• Nausea, vomiting and abdominal pain

• Headache, fatigue and diarrhea have been

reported commonly with prophylactic use.

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 ANTI HEPATITIS AGENTS
• Current agents are SUPPRESIVE rather than curative

• Efficacy end points in clinical trials of hepatitis B virus (HBV)

infection are seroconversion of HBeAg from positive to
negative and suppression of HBV DNA to undetectable
levels.

• These end points are correlated with

1. improvement in necroinflammatory disease,
2. a decreased risk of hepatocellular carcinoma and
3. cirrhosis, and
4. a decreased need for liver transplantation

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• Three oral nucleoside agents are currently used in
mgt of Hepatitis B: emtricitabine, lamivudine and
tenofovir

• Injectable interferon drugs are also used

• NRTI agents may be used in patients co-infected with

hepatitis B and HIV, it is important to note that acute
exacerbation of hepatitis may occur upon
discontinuation or interruption of these agents
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 1. Lamivudine
• Lamivudine inhibits HBV DNA polymerase and
HIV reverse transcriptase by competing with
deoxycytidine triphosphate for incorporation
into the viral DNA, resulting in chain
termination

• The more prolonged intracellular half-life in

HBV cell lines (17–19 hours) than in HIV-
infected cell lines (10.5–15.5 hours) allows for
lower doses and less frequent administration
(100mg per day) with HBV infection
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• Continuation of treatment for 4–8 months
AFTER seroconversion of HBeAg from positive
to negative may improve the durability of
response.

• Chronic therapy with lamivudine in patients

with hepatitis may ultimately be limited by
the emergence of lamivudine-resistant HBV
isolates

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• Cross-resistance between lamivudine and
either emtricitabine or entecavir may occur;
however, cross-resistance between lamivudine
and adefovir has NOT been reported.

• Adverse effects (refer to HIV notes)

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 2. Adefovir
• Adefovir dipivoxil is the diester pro-drug of
adefovir, an acyclic phosphonated adenine
nucleotide analog

• It is phosphorylated by cellular kinases to the

active diphosphate metabolite and then
competitively inhibits HBV DNA polymerase
to result in chain termination after
incorporation into the viral DNA

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• Oral bioavailability is about 59% and is
unaffected by meals

• The terminal elimination half-life is

approximately 7.5 hours.

• Adefovir is excreted by a combination of

glomerular filtration and active tubular
secretion and thus may be administered to
patients with decompensated liver disease.
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 Adverse effects
• Adefovir dipivoxil is well tolerated.

• A dose-dependent nephrotoxicity has been

observed in clinical trials

• Headache, diarrhea, asthenia, and abdominal pain

• As with other NRTI agents, lactic acidosis and

hepatic steatosis are considered a risk owing to
mitochondrial dysfunction.
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 3. Entecavir
• An orally administered guanosine nucleoside
analog

• 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

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• Oral bioavailability approaches 100% but is decreased by food;
therefore, entecavir should be taken on an empty stomach

• The intracellular half-life of the active phosphorylated

compound is 15 hours

• It is excreted by the kidney, undergoing both glomerular

filtration and net tubular secretion

• Entecavir is well tolerated. The most frequently reported

adverse events are headache, fatigue, dizziness, and nausea

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 4. Interferon alpha
• Interferons are host cytokines that exert
complex
1. antiviral,
2. immunomodulatory, and
3. antiproliferative activities

• Injectable preparations of interferon alfa are

available for treatment of both HBV and HCV
virus infections

• Interferon alfa may be administered SC or IM

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• Elimination half-life is 2–5 hours depending on
the route of administration.

• Alfa interferons are filtered at the glomeruli

and undergo rapid proteolytic degradation
during tubular reabsorption

• Liver metabolism and subsequent biliary

excretion are considered minor pathways.

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• PEGYLATED interferon alfa-2a and pegylated
interferon alfa-2b have recently been
introduced for the treatment of patients with
HBV and HCV infections

• Slower clearance of these agents results in

substantially longer terminal half-lives and
steadier drug concentrations, allowing for less
frequent dosing.

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 Adverse effects
• Typical side effects of interferon alfa include a flu-like
syndrome (ie, headache, fevers, chills, myalgias, and malaise,
transient hepatic enzyme elevations may occur in the first 8–12
weeks of therapy

• Potential adverse effects during chronic therapy include

neurotoxicities (mood disorders, depression, somnolence,
confusion, seizures), myelosuppression, profound fatigue,
weight loss, rash, cough, myalgia, alopecia, tinnitus, reversible
hearing loss, retinopathy, pneumonitis, and possibly
cardiotoxicity.

• Induction of autoantibodies may occur, causing exacerbation or

unmasking of autoimmune or thyroid disease
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 Contraindications
• Hepatic decompensation, autoimmune
disease, and history of cardiac arrhythmia

• Alfa interferons are abortifacient in primates

and should not be administered in pregnancy

• Caution is advised in the setting of psychiatric

disease, epilepsy, thyroid disease, ischemic
cardiac disease, severe renal insufficiency, and
cytopenia
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 Drug interactions
• Potential drug-drug interactions include increased
theophylline levels and increased methadone
levels

• Combination therapy with NRTI agents may

cause hepatic failure; in particular, co-
administration with didanosine is not
recommended.

• Co-administration with zidovudine may exacerbate

cytopenias. 73
 5. Ribavirin
• Ribavirin is a guanosine analog that is
phosphorylated intracellularly by host cell
enzymes

• It appears to interfere with the synthesis of

guanosine triphosphate, to inhibit capping of
viral messenger RNA, and to inhibit the viral
RNA-dependent polymerase of certain viruses

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• Ribavirin triphosphate inhibits the replication
of a wide range of DNA and RNA viruses,
including
• influenza A and B,
• parainfluenza,
• respiratory syncytial virus,
• paramyxoviruses,
• HCV, and
• HIV-1.

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• The absolute oral bioavailability of ribavirin is about
64%, increases with high-fat meals, and decreases
with co-administration of antacids

• Ribavirin elimination is primarily through the urine

• Evidence suggests that both a higher dose (ie, > 10.6

mg/kg) and a longer duration of ribavirin therapy, in
combination with one of the interferon alfas, may
IMPROVE RESPONSE
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 Adverse effects
• Adverse effects include a dose-dependent
hemolytic anemia occurs in 10–20% of
patients, depression, fatigue, irritability, rash,
cough, insomnia, nausea, and pruritus

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 Contraindications
• Contraindications to ribavirin therapy include
uncorrected anemia, end-stage renal failure,
ischemic vascular disease, and pregnancy.

• Ribavirin is teratogenic and embryotoxic in

animals as well as mutagenic in mammalian cells.

• Patients exposed to the drug should NOT

conceive children for at least 6 months thereafter.
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THANK YOU
79