ANTIVIRAL AGENTS

Rianto Setiabudy
& Dewi Selvina Rosdiana
Dept. of Pharmacology, FMUI
Lecture for Module of Infection and Immunology,
April,2012
 Objectives of this discussion
1. To understand the life cycle of viruses
in hosts cell
2. To understand the mechanism of
actions of antiviral agents
3. To know the classification of antiviral
agents
4. To know the pharmacology of some
important antiviral agents
 Outline of discussion
Classification of antiviral agents
Life cycle of virus in host cell
Antiretroviral (HIV) agents
Antivirals for and cytomegalovirus
(CMV) infections
Antivirals for respiratory tract infections
Antivirals for herpes simplex virus (HSV)
Antivirals for hepatitis
Classification of oral antiviral agents
Agents to treat herpes simplex virus &
varicella zoster virus infections: acyclovir,
valacyclovir, famcyclovir
Agents to treat cytomegalovirus (CMV)
infections: gancyclovir, cidovofir, foscarnet,
fomivirsen
Anti retroviral (HIV) agents
Anti-hepatitis agents
Anti-influenza agents
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Life cycle of virus in host cell
Adsorption to and penetration into cell
Uncoating of viral nucleic acid
Synthesis of regulatory proteins
Synthesis of viral RNA or DNA
Synthesis of structural proteins
Assembly of viral particles
Release from the cell
 Life cycle of virus in host cell
Enfuvirtide amantadine

Penetration Uncoating
adsorption Early protein synthesis
purine or
Nucleic acid synthesis
pyrimidine analogs
Late protein synthesis and processing

Packaging and assembly protease

inhibitors
Viral release
Neuraminidase
inhibitors
 Life cycle of virus in host cell

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Antiretroviral agents
 Antiretroviral (HIV) agents (1)
Classification:
1. Nucleoside reverse transcriptase inhibitors
(NRTIs):
e.g., zidovudine, lamivudine, zalcitabine,
stavudine, abacavir
2. Non-nucleoside reverse transcriptase inhibitors
(NNRTIs):
e.g., nevirapine, efavirenz, delavirdine
Antiretroviral (HIV) agents (1)
3. Protease inhibitors (PIs):
e.g., saquinavir, ritonavir, indinavir,
nelvinavir, amprenavir
4. Fusion inhibitors: e.g., enfuvirtide
5. Integrase inhibitor: raltegravir
6. Chemokine receptor antagonist: maraviroc
Note: Groups of drug printed in red are metabolized by
CYP3A4 potentially have drug interaction problems
 Reverse transcriptase and protease
in retroviruses
Enfuvirtide
(fusion inhibitor)
Blocked by reverse
Viral RNA
transcriptase inhibitors
Reverse transcriptase
Blocked by Viral DNA
integrase inhibitors
Host DNA

Precursor polyprotein

Viral RNA Blocked by

Viral proteins protease
inhibitors
 Antiretroviral (HIV) agents:
The NRTI
1. Zidovudine
Administration: oral
Indication: HIV infection
Prolongs patient survival
Activated to its triphosphate derivative by
mammalian thymidine kinase inhibits viral
reverse transcriptase terminates viral DNA
synthesis
Pregnant woman: may suppress vertical
transmission of the HIV virus
 Antiretroviral (HIV) agents:
The NRTI

Side effects: myelosuppresion, nausea,

insomnia
Drug interactions: avoid concomitant
administration with other myelosuppressants
(gancyclovir, ribavirin, etc.)
 Antiretroviral (HIV) agents:
The NRTI

2. Lamivudine
Also requires triphosphorylation for
activation
Terminates the synthesis of viral DNA
Works synergistically with zidovudine
Indications: HIV and hepatitis B virus
infections
Side effects: insomnia, fatigue
 Antiretroviral (HIV) agents:
The NRTI

3. Zalcitabin
Also requires triphosphorylation for
activation
Terminates the synthesis of viral DNA
Least effective but inexpensive
Side effect: peripheral neuropathy,
esophageal ulceration
 Antiretroviral (HIV) agents:
The NRTI
4. Stavudine
Also requires triphosphorylation for activation
Mode of action: RTI and as a chain terminator
Main side effect: peripheral neuropathy
5. Didanosine
Mode of action: terminates DNA synthesis
Main side effects: peripheral neuropathy and
pancreatitis
 Antiretroviral (HIV) agents:
The NNRTI
1. Nevirapine
Indicated for HIV-1 infection in adults and
children
Used in combination with other agents
2. Efavirenz
Shows good effects in combination with other
antiviral agents
Side effects: CNS complaints, skin rash,
teratogenic in animal studies
 Antiretroviral (HIV) agents:
The Protease inhibitors
1. Saquinavir
Inhibits the activity of HIV-1 protease
When given in combination with RTIs
additive or synergistic effect
Poor oral bioavailability, meal improves
absorption
Rifampin & rifabutin decrease blood levels of
saquinavir
Side effect: gastrointestinal discomfort
 Antiretroviral (HIV) agents :
The Protease inhibitors
2. Indinavir
Inhibits protease of HIV-1, the essential
enzyme for for the production of mature
virions
Used in combination with an RTI to delay
emergence of resistance
Side effects: hyperbilirubinemia,
nephrolithiasis
Instruction for patients: drink much water
 Antiretroviral (HIV) agents :
Protease inhibitors
3. Ritonavir:
Strongly inhibits CYP3A4 interactions with many
other drugs
Commonly combined with other agents (lopinavir,
indinavir, amprenavir) to increase their T1/2s
time of exposure to drug reduce resistance
Side effects: gastrointestinal disturbances,
hypertriglyceridemia, peripheral or circumoral
paresthesia
Principles of antiretroviral therapy
1. Give combination of 3 drugs in initial
therapy
2. If possible, avoid using drugs to which the
patient has been exposed to before
3. Avoid combining drugs with overlapping
toxicities (e.g. zalcitabine, stavudine,
didanosine peripheral neuropathy)
4. Avoid giving drugs which are contra-
indicated to the patient
5. Avoid giving drugs which produce
undesirable interaction
Principles of antiretroviral therapy
(contd)

6. First line treatment: start with 2 NRTIs (e.g.

zidovudine & lamivudine) + 1 NNRTI (e.g.
nevirapine) or a PI (e.g. indinavir)
7. If the combination fails, return to point 1
and use at least 2 drugs the patient has
never got before or consider a second-line
treatment
 Side effects commonly associated
with ARV therapy (1)
Side effect Commonly caused by
lipodystrophy NRTIs: especially stavudine, zidovudine
anemia zidovudine
peripheral neuropathy stavudine, didanosine
insulin resistance PIs
nephrotoxicity tenovovir
pancreatitis stavudine, didanosine
lactic acidosis NRTIs: especially stavudine, didanosine
Side effects commonly associated
with ARV therapy (2)

Side effect Commonly caused by

loss of appetite abacavir
hepatotoxicity nevirapine, ritonavir
fatigue zidovudine
Lipodystrophy
Agents to treat Cytomegalovirus
infections
Agents to treat CMV infections (1)

CMV infections:
In congenital infections: associated with
severe birth defects
In immune-compromised individuals :
retinitis, colitis, gastritis, hepatitis,
pneumonitis
Commonly found in HIV patients
Agents to treat CMV infections (2)
1. Gancyclovir:
Route of administration: IV, oral, intraocular implant
Often combined with foscarnet for treatment of CMV
retinitis in patients with AIDS.
Resistance is more likely to occur in longer use
Important side effect: myelosuppression, gastro
intestinal and CNS complaints

2. Valgancyclovir:
Well absorbed after oral administration
Indicated for the treatment of CMV retinitis in
patients with AIDS
Side effects: similar to gancyclovir
Agents to treat CMV infections (3)
3. Foscarnet:
Given intravenously or intravitreally
Prolonged therapy point mutation at the DNA
polymerase gene
Potential side effects: renal impairment,
hyper/hypocalcemia, penile ulceration

4. Cidofovir:
Given intravenously
Activation is dependent on viral enzymes
Its active metabolites have long T (17-65 hours)
Side effect: dose dependent nephrotoxicity avoid
to combine it with other nephrotoxic agents
Anti-influenza agents
 Anti-influenza agents
Zanamivir and oseltamivir:
Inhibit viral neuraminidase
Active against both influenza A and B viruses
Zanamivir is given by inhalation, while oseltamivir
by oral route
Oseltamivir is now also used for the treatment of
avian flu but its efficacy is disappointing
AEs of oseltamivir: nausea, vomiting, abdominal
pain
Treatment should be started not later than 72 h
after the onset of illness
Antivirals against herpes simplex
virus
 Drugs to treat herpes simplex virus
and varicella-zoster virus (1)

Acyclovir
Valacyclovir
Famcyclovir
Pencyclovir
Drugs to treat herpes simplex virus
and varicella-zoster virus (2)
Acyclovir:
Prodrug activated by viral triphosphate
(active)
Mechanism: inhibits viral DNA polymerase
Dosage: - Genital herpes 5 x 200 mg/day
- Herpes zoster 5 x 400 mg/day
- Varicella 4 x 400 mg/day
SE: well tolerated, sometimes nausea,
diarrhea, headache

Valacyclovir:
Better bioavailability than acyclovir
Antivirals for hepatitis
 Drugs for hepatitis B (1)
1. Interferron alfa
Interferrons are host cytokines immuno-
modulatory, antiproliferative, and antiviral effects
Interferrons alfa -2a and -2b are to be given
subcutaneously
Pegylated interferrons have longer T allow
less frequent dosing
SE: transient flu-like syndrome, fatigue,
neurotoxicity
CI: hepatic decompensation, autoimmune diseases,
cardiac arrhytmia, pregnancy
Interactions: +NRTIs hepatic failure
+ zidovudine cytopenia
 Drugs for hepatitis B (2)
2. Lamivudine
Inhibits HBV DNA polymerase and HIV reverse
transcriptase
Well tolerated
Chronic therapy resistance problem

3. Entecavir
Good bioavailability
Resistance rate is lower than that of lamivudine
Generally well tolerated
SE: headache, fatigue, dizziness
Interaction: + drugs which reduce renal function
serum concentration of both drugs may increase
 Drugs for hepatitis B (3)
4. Adefovir dipivoxil
Competitively inhibits HBV DNA polymerase
chain termination
Oral bioavailability: fairly good, not affected by
meals
Main excretion: kidneys
Resistance: rare. No cross-resistance with
lamivudine
Safety:
Well tolerated
Common side effects: headache, diarrhea,
abdominal pain
Embryotoxic in rats
 Drugs for hepatitis C
Ribavirin:
Used in combination with interferron alfa
Mechanism of action: inhibits the synthesis of
guanosine triphosphate
Oral bioavailability: fairly good
Absorption is decreased by antacids and
increased by fatty meals
SE: hemolytic anemia, depression, fatigue
CI: anemia, end state renal failure, ischemic
vascular disease, pregnancy (teratogenic in
animals)
Thank you