The Pharmacology of

Antiviral Agents

Rianto Setiabudy
Dept. of Pharmacology, FMUI
Lecture for Module of Infection and Immunology,
1 March 2016
 Objectives of this discussion
1. To understand the life cycle of viruses
in host’s 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
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 pyrimidine
Nucleic acid synthesis
analogs
Late protein synthesis and processing

Packaging and assembly

protease
inhibitors
Viral release
Neuraminidase
inhibitors
Antiretroviral agents
Reverse transcriptase and protease
in retroviruses
Blocked by fusion
inhibitor
Blocked by reverse
transcriptase inhibitors Viral RNA
Reverse transcriptase
Blocked by integrase Viral DNA
inhibitors
Host DNA

Precursor polyprotein

Viral RNA Blocked by

protease
Viral proteins inhibitors
 Antiretroviral (HIV) agents (1)
Classification:
1. Nucleoside reverse transcriptase inhibitors
(NRTIs):
e.g., zidovudine, lamivudine, stavudine,
tenofovir, emtricitabine, etc.
2. Non-nucleoside reverse transcriptase inhibitors
(NNRTIs):
e.g., nevirapine, efavirenz
Antiretroviral (HIV) agents (1)
3. Protease inhibitors (PIs):
e.g., saquinavir, ritonavir, indinavir,
nelvinavir, amprenavir
4. Fusion inhibitors: e.g., enfuvirtide, maraviroc
5. Integrase inhibitor: raltegravir
 Antiretroviral (HIV) agents:
The NRTI

1. Zidovudine (AZT)
– 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 (3TC)
– Also requires triphosphorylation for activation
– Terminates the synthesis of viral DNA
– Works synergistically with zidovudine
– Indications: HIV and hepatitis B virus
infections
– Side effects: well tolerated but may cause
insomnia, fatigue
 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  contraindicated in
the first trimester of pregnancy
 Antiretroviral (HIV) agents:
The Protease inhibitors
1. Saquinavir
2. Indinavir
3. Nelvinavir
4. Lopinavir + ritonavir (Aluvia®, Kaletra®)
5. Amprenavir , etc.
 Some notes for antiretroviral
therapy
1. Give combination of 3 drugs in initial therapy , i.e.: 2
NRTIs + 1 NNRTI
2. Start treatment if:
– CD4 count < 350 cells/mm3 or
– Co-infection with tuberculosis or
– Co-infection with hepatitis B chronic active or
– Pregnancy or breastfeeding
– Clinical stadium 3 or 4
3. Efavirenz (EFV) is contraindicated in trimester 1 of
pregnancy
4. Stavudine (d4T) is being phased out because of lactic
acidosis, lipodystrophy, and peripheral neuropathy
 Some notes for antiretroviral
therapy (cont’d)
5. For first line treatment: start with:
2 NRTIs: AZT (or TDF) and 3TC (or FTC) plus
1 NNRTI : NVP or EFV
6. Do not use a PI as first line treatment
7. Once ART is started, it should be continued for the
rest of the patient’s life, unless a very severe side
effects occurs

Note: AZT=zidovudine, TDF=tenofovir, 3TC=lamivudine,

FTC=emtricitabine, NVP=nevirapine, EFV=efavirenz
 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 protease inhibitors
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 or oral
– Often combined with foscarnet
– 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 T½
– 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 thymidine kinase
 acyclovir triphosphate
 Mechanism: inhibits viral DNA polymerase
 Dosage: - Genital herpes 5 x 200 mg/day
- Herpes zoster 5 x 400-800 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 T½  allow a
once weekly dosing
 SE: transient flu-like syndrome, fatigue, neuro-
toxicity
 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
 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 and interferron:
 Ribavirin is always used in combination with
interferron alfa
 Today inteferon has been mostly replaced by
pegylated interferron  once weekly (IM)
administration
 SE: hemolytic anemia, depression, fatigue
 CI: anemia, end state renal failure, ischemic
vascular disease, pregnancy (teratogenic in
animals)
 Sustained virological response (SVR) is only 50%
 Side effects are troublesome
 Drugs for hepatitis C
Direct acting antivirus (DAA):
– NS3/4A inhibitors (= protease inhibitor):
telaprevir, boceprevir, simeprevir
– NS5A inhibitors: daclatasvir, ledipasvir,
ombitasvir
– NS5 inhibitors (= polymerase inhibitors):
sofosbuvir, dasabuvir
 Today, the combination of various DAAs or a DAA
+ interferon/ribavirin just for 12-24 weeks can
achieve sustained virological response (SVR)
 Examples:
– Interferron/ribavirin + sofosbuvir
– Sofosbuvir + ledipasvir
Thank you