ANTIVIRAL

A N G G E L I A P U S PA S A R I , M D
D E P T. P H A R M A C O L O G Y A N D T H E R A P E U T I C
M E D I C A L FA C U LT Y U N I V E R S I T Y O F J A M B I

ANGGELIA P, MD. PHARMACOLOGY AND THERAPEUTIC DEPT.

INTRODUCING
Viruses are obligate intracellular parasites

antiviral agents must either block viral entry into or exit from the cell
or be active inside the host cell

may interfere with host cell function and produce toxicity

Recent research has focused on the identification of agents with
greater selectivity, in vivo stability, and lack of toxicity
INTRODUCING (MECHANISM OF ACTION)
CLASSES
I. Anti Herpes Group:
Idoxuridine, Acyclovir, Famciclovir, Ganciclovir, Valacyclovir, Famciclovir, Penciclovir,Valganciclovir, Cidofovir,
Foscarnet, Fomivirsen
II. Antiretroviral drugs
 a) Nucleoside reverse transcriptase inhibitors (NRTIs), Zidovudine, Didanosine, Zalcitabine, Stavudine,
Lamivudine, Abcavir
 b) Nucleotide inhibitors – Tenofovir
 c) Non-nucleoside reverse transcriptase inhibitors (NNRTIs) – Delaviridine, Nevirapine, Efavirenz
 d) Protease inhibitors – saquinavir, Ritonavir, Indinavir, Nelfinavir, Amprenavir
 e) Fusion inhibitors – Enfuvirtide
III. Antiinfluenzal
 Amantadine, Rimantidine, Zanamivir, Osletamivir
IV. Antihepatitis
Lamivudine, Adefovir, Ribavarin, Interferon
V. Other drugs
Plecoranil, Palivizumab, Imiquimod
Antiherpetic agent
ANTIHERPETIC AGENT

 Three oral nucleoside analogs are licensed for the treatment of

HSV and VZV infections: acyclovir, valacyclovir, and famciclovir.
 They have similar mechanisms of action and similar indications
for clinical use; all are well tolerated.
 modest superiority of famciclovir and valacyclovir over acyclovir
for the treatment of herpes zoster.
ANTIHERPETIC AGENT
ACYCLOVIR
 Acyclic guanosine derivative with clinical activity against HSV-1,
HSV-2, and VZV
 Acyclovir requires three phosphorylation steps for activation. It is
converted first to the monophosphate derivative by the virus-
specified thymidine kinase and then to the di- and triphosphate
compounds by host cell enzymes
 Acyclovir triphosphate inhibits viral DNA synthesis
ANTIHERPETIC AGENT
ACYCLOVIR
 The bioavailability of oral acyclovir is 15–20% and is unaffected
by food.
 Acyclovir is cleared primarily by glomerular filtration and tubular
secretion. The half-life is approximately 3 hours in patients with
normal renal function and 20 hours in patients with anuria.
 Acyclovir diffuses readily into most tissues and body fluids.
Cerebrospinal fluid concentrations are 50% of serum values.
ANTIHERPETIC AGENT
VALACYCLOVIR

 Valacyclovir is the L-valyl ester of acyclovir

 Serum levels that are three to five times greater than those
achieved with oral acyclovir and approximate those achieved with
intravenous acyclovir administration.
 Oral bioavailability is 54%, and cerebrospinal fluid levels are 50%
of those in serum.
 Elimination half-life is 2.5–3.3 hours.
ANTIHERPETIC AGENT
FAMCICLOVIR
• Famciclovir is the diacetyl ester prodrug of 6-deoxypenciclovir, an acyclic
guanosine analog .
• Penciclovir triphosphate has lower affinity for the viral DNA polymerase
than acyclovir triphosphate, but it achieves higher intracellular
concentrations and has a more prolonged intracellular effect in
experimental systems.
• The bioavailability of penciclovir from orally administered famciclovir is
70%.
• Penciclovir triphosphate has an intracellular half-life of 10 hours in HSV-
1-infected cells, 20 hours in HSV-2-infected cells, and 7 hours in VZV-
infected cells in vitro.
• Penciclovir is excreted primarily in the urine.
ANTIHERPETIC AGENT

PENCICLOVIR
 Active metabolite of famciclovir
 1% penciclovir cream….recurrent herpes labialis
DOCOSANOL
 Docosanol is a saturated 22-carbon aliphatic alcohol, preventing viral entry into
cells and subsequent viral replication.
 Topical docosanol 10% cream is available without a prescription.
TRIFLURIDINE
 Trifluridine (trifluorothymidine) is a fluorinated pyrimidine nucleoside
 1% solution is effective in treating keratoconjunctivitis and recurrent epithelial
keratitis due to HSV-1 and HSV-2.
POSOLOGI
acyclovir:
 Tablet 400 mg (merk….)
 Dosis dan indikasi : varicella 4x800 mg selama 5 hari
zoster 5x800 mg selama 7-10 hari
Kontra indikasi ??????
Efek samping obat ??????
Kehamilan dan menyusui ?????
TUGASSSSSSS
ANTIRETRO VIRAL AGENT
ANTIRETRO VIRAL AGENT

 Four classes of antiretroviral agents are available for use: nucleoside/nucleotide

reverse transcriptase inhibitors (NRTIs), nonnucleoside reverse transcriptase
inhibitors (NNRTIs), protease inhibitors (PIs), and fusion inhibitors
 Extreme polypharmacy necessitates awareness of pharmacokinetic and
pharmacodynamic interactions.
 HAART (highly active antiretroviral therapy): 2 NRTI+1 NNRTI/1 PI
Ex: AZT+3 TC+nevirapine or tenofovir+3TC+aluvia (lopinavir/r)
NUCLEOSIDE & NUCLEOTIDE REVERSE TRANSCRIPTASE
INHIBITORS (NRTI)

 The NRTIs act by competitive inhibition of HIV-1 reverse

transcriptase and incorporated into the growing viral DNA chain
to cause termination
 Most have activity against HIV-2 as well as HIV-1.
 Nucleoside analogs may be associated with mitochondrial
toxicity, Increase the risk of lactic acidosis with hepatic steatosis
 Agent: abacavir, didanosine (ddI), emtricitabacavir, abine,
lamivudine (3TC), stavudine (d4T), tenofovir, zalcitabine,
zidovudine (AZT)
ZIDOVUDINE (AZT)

 Azidothymidine, deoxythymidine analog

 well absorbed from the gut and distributed to most body tissues and fluids,
including the cerebrospinal fluid
 serum half-life averages 1 hour, and the intracellular half-life of the
phosphorylated compound is 3–7 hours.
 eliminated primarily by renal excretion following glucuronidation in the liver
 The most common adverse effect of zidovudine is myelosuppression, resulting in
macrocytic anemia (1–4%) or neutropenia (2–8%).
 Hematologic toxicity may be increased (probenecid, acetaminophen, lorazepam,
indometachin, cimetidine, ganciclovir, ribavirin, and cytotoxic agents)
 Zidovudine (AZT) and stavudine (D4T)….. antagonism has been demonstrated in
vitro ( AZT reduce the phosphorylation of stavudine)
STAVUDINE (D4T)
 Thymidine analog
 Has high oral bioavailability (86%) that is not food-dependent
 The plasma half-life is 1.2 hours, the intracellular half-life is approximately 3.5
hours
 Excretion is by active tubular secretion and glomerular filtration.
 Dosage of stavudine should be reduced in patients with renal insufficiency and
low body weight.
 The major dose-limiting toxicity is a dose-related peripheral sensory neuropathy.
The incidence of neuropathy may be increased when stavudine is administered
with other neuropathy-inducing drugs such as didanosine and zalcitabine.
LAMIVUDINE (3TC)
 Cytosine analog
 Synergistic with a variety of antiretroviral nucleoside analogs—including
zidovudine and stavudine—against both zidovudine-sensitive and zidovudine-
resistant HIV-1 strains
 Oral bioavailability exceeds 80% and is not food-dependent.
 The majority of lamivudine is eliminated unchanged in the urine, and the dose
should be reduced in patients with renal insufficiency or low body weight.
 Potential adverse effects are headache, insomnia, fatigue, and gastrointestinal
discomfort, although these are typically mild
 Lamivudine and zalcitabine may inhibit the intracellular phosphorylation of one
another in vitro (decreasing potency)
DIDANOSINE (DDI)
 Synthetic analog of deoxyadenosine
 Oral bioavailability is 30–40%; dosing on an empty stomach is required.
Cerebrospinal fluid concentrations of the drug are approximately 20% of serum
concentrations.
 Elimination half-life is 1.5 hours, but the intracellular half-life of the activated
compound is as long as 20–24 hours.
 Eliminated by glomerular filtration and tubular secretion.
 The major clinical toxicity associated with didanosine therapy is dose-dependent
pancreatitis (zalcitabine and stavudine avoided)
 adverse effects include painful peripheral distal neuropathy, diarrhea (particularly
with tablets and powder), hepatitis, esophageal ulceration, cardiomyopathy, and
central nervous system toxicity (headache, irritability, insomnia)
TENOFOVIR
 Acyclic nucleoside phosphonate (ie, nucleotide) analog of adenosine
 The oral bioavailability in fasted patients is approximately 25% and increases to
39% after a high-fat meal.
 Serum half-life is 17 hours and intracellular half-life is prolonged at more than 60
hours.
 Elimination occurs by a combination of glomerular filtration and active tubular
secretion
 Gastrointestinal complaints (eg, nausea, diarrhea, vomiting, flatulence)
 The combination of tenofovir with didanosine is associated with both decreased
virologic efficacy and increased toxicity (due to increased didanosine levels) and
therefore should be avoided
NONNUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS (NNRTI)

 The NNRTIs bind directly to HIV-1 reverse transcriptase , resulting

in blockade of RNA- and DNA-dependent DNA polymerase.
 Unlike the NRTI agents, NNRTIs neither compete with nucleoside
triphosphates nor require phosphorylation to be active.
 Adverse effect gastrointestinal intolerance and skin rash, the
latter of which may infrequently be serious (eg, Stevens-Johnson
syndrome).
 A further limitation to use of NNRTI agents as a component of
HAART is their metabolism by the CYP450 system, leading to
innumerable potential drug-drug interactions.
 Agent; delavirdine, efavirenz, nevirapine
EFAVIRENZ
 Efavirenz long half-life (40–55 hours).
 It is moderately well absorbed following oral administration (45%).
 Toxicity may increase owing to increased bioavailability after a high-fat meal,
efavirenz should be taken on an empty stomach.
 The principal adverse effects of efavirenz involve the central nervous system
(dizziness, drowsiness, insomnia, headache, confusion, amnesia, agitation,
delusions, depression, nightmares, euphoria); these may occur in up to 50% of
patients and may be severe. However, they tend to resolve after the first month of
treatment..
NEVIRAPINE

 The oral bioavailability of nevirapine is excellent (~ 90%) and is not food-

dependent. The drug is highly lipophilic and achieves cerebrospinal fluid levels
that are 45% of those in plasma.
 Serum half-life is 25–30 hours.
 It is extensively metabolized by the CYP3A isoform to hydroxylated metabolites
and then excreted, primarily in the urine.
 Rash occurs in approximately 17% of patients, most typically in the first 4–6
weeks of therapy, and is dose-limiting in about 7% of patients.
 Women may have a greater propensity for rash. Severe and life-threatening skin
rashes have been rarely reported, including Stevens-Johnson syndrome and toxic
epidermal necrolysis.
 Nevirapine therapy should be immediately discontinued in patients with severe
rash and in those with accompanying constitutional symptoms.
PROTEASE INHIBITORS

 Preventing cleavage of the Gag-Pol polyprotein, protease inhibitors (PIs) result in

the production of immature, noninfectious viral particles
 A syndrome of redistribution and accumulation of body fat that results in central
obesity, dorsocervical fat enlargement (buffalo hump), peripheral and facial
wasting, breast enlargement, and a cushingoid appearance has been observed in
patients receiving antiretroviral therapy..
 Protease inhibitors have been associated with increased spontaneous bleeding in
patients with hemophilia A or B.
 All of the antiretroviral PIs are substrates and inhibitors of CYP3A4, with ritonavir
having the most pronounced inhibitory effect and saquinavir the least.
LOPINAVIR/RITONAVIR
 Absorption of lopinavir is enhanced with food.
 The oral solution contains alcohol.
 Lopinavir is extensively metabolized by the CYP3A isozyme of the
hepatic cytochrome P450 system, which is inhibited by ritonavir.
 The most common adverse effects of lopinavir are diarrhea,
abdominal pain, nausea, vomiting, and asthenia.
 Increased dosage of lopinavir/ritonavir is recommended when
co-administered with efavirenz or nevirapine, which induce
lopinavir metabolism.
Interferon
INTERFERON

 Interferons are host cytokines that exert complex antiviral, immunomodulatory, and
antiproliferative activities
 Injectable preparations of interferon alfa are available for treatment of both HBV and
HCV virus infections
 Interferon alfa-2a and interferon alfa-2b may be administered subcutaneously or
intramuscularly, whereas interferon alfacon-1 is administered subcutaneously.
Elimination half-life is 2–5 hours for interferon alfa-2a and -2b, depending on the route
of administration.
 Typical side effects of interferon alfa include a flu-like syndrome
 Transient hepatic enzyme elevations may occur in the first 8–12 weeks of therapy and
appear to be more common in responders.
 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.
INTERFERON
 Contraindications to interferon alfa therapy include hepatic decompensation,
autoimmune disease, and history of cardiac arrhythmia
 Alfa interferons are abortifacient in primates and should not be administered in
pregnancy
 Combination therapy with NRTI agents may cause hepatic failure (co-
administration with didanosine is not recommended)
 Co-administration with zidovudine may exacerbate cytopenias.
 Buatlah profil farmakokinetik antivirus yang digunakan untuk terapi virus influenza
dan hepatitis B kronik!
Terimakasih