ANTIVIRAL

Anggelia Puspasari, MD
Dept. Pharmacology and Therapeutic
Medical Faculty University of Jambi

Anggelia P, MD. Pharmacology and

Therapeutic Dept.
 introducing
• Viruses are obligate intracellular parasites

• antiviral agents must baik memblock viral entry into or exit from the cell
or be active inside the host cell

• Dapat menganggu with host cell function and produce toxicity

• Penelitian baru-baru ini has focused on the identification of agents with
greater selectivity, in vivo stability, and mengurangi 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, Tenofovir
– b) Nucleotide inhibitors –c) Non-nucleoside reverse transcriptase inhibitors
(NNRTIs) – Delaviridine, Nevirapine, Efavirenz
– d) Protease inhibitors – saquinavir, Ritonavir, Indinavir, Nelfinavir, Amprenavir;
second generation (darunavir)
– e) Fusion inhibitors – Enfuvirtide
– f) HIV integrase inhibtor-Raltegavir
• III. Antiinfluenzal
– Amantadine, Rimantidine, Zanamivir, Osletamivir
• IV. Antihepatitis
• Lamivudine, Adefovir, Ribavarin, Interferon
• V. Other drugs
• Plecoranil, Palivizumab, Imiquimod
 Antiherpetic agent
 Three oral nucleoside analogs are bisa 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.
 Sederhana superiority of famciclovir and valacyclovir over
acyclovir for the treatment of herpes zoster. They ditingkatkan
penyembuhan lesion and decreased or stop pain frequently
terkait with herpes lesion.
 Topical acyclovir in herpes simplex treatment is secara
signifikan kurang effective but will shorten healing time and
duration of viral penyebaran and pain in patient with initial
pecahnya of herpes.
 Antiherpetic agent
acyclovir

 Acyclic guanosine derivative with clinical activity

melawan HSV-1, HSV-2, and VZV
 Acyclovir membutuhkan three phosphorylation steps
for activation. Pertama dia diubah to the
monophosphate derivative (turunan) by the virus-
specified thymidine kinase and then to the di- and
triphosphate senyawa by host cell enzymes
 Acyclovir triphosphate inhibits viral DNA synthesis
 Antiherpetic agent
acyclovir

 The bioavailability of oral acyclovir is 15–20% and is

dipengaruhi by food.
 Acyclovir is dibersihkan terutama by glomerular
filtration and tubular secretion. Waktu paruhnya 3
hours in patients with normal renal function and 20
hours in patients with anuria.
 Acyclovir berdifusi cepat into most tissues and body
fluids. Cerebrospinal fluid concentrations are 50% of
nilai serum.
 Antiherpetic agent
VALACYCLOVIR

 Valacyclovir is the L-valyl ester of acyclovir

 Kadar serum 3-5x lebih besar dari pada yang di capai
with oral acyclovir and perkiraann yang di capai 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 ketimbang acyclovir triphosphate, but
it achieves higher intracellular concentrations and has
lebih lama intracellular effect in experimental systems.
• The bioavailability of penciclovir from famciclovir oral is
70%.
• Penciclovir triphosphate has an intracellular half-life of
10 hours in HSV-1-sel yang diinfeksi, 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 viral replication.
 Topical docosanol 10% cream is available without a
resep.
• 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.
• 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), fusion
inhibitors and HIV integrase inhibitor
 Polifarmasi harus tahu of pharmacokinetic and
pharmacodynamic interactions.
 HAART (highly active antiretroviral therapy): 2 NRTI+1
NNRTI/1 PI
•Ex: AZT+3 TC+nevirapine or tenofovir+3TC+lopinavir
Nucleoside & Nucleotide Reverse Transcriptase Inhibitors (NRTI)

 The NRTIs bekerja dengan competitive inhibition of

HIV-1 reverse transcriptase and tergabung into the
growing viral DNA rantai to memutuskannya.
 Sebagain besar memiliki aktivitas terhadap HIV-2 dan
HIV-1.
 Nucleoside analogs may be terkait with
mitochondrial toxicity, Increase the resko 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 rata-rata 1 hour, and the intracellular half-life of the
phosphorylated senyawa is 3–7 hours.
 eliminated terutama by renal excretion following glucuronidation in the
liver
 The most common effect berlawanan 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%) tidak bergantung pd
makanan
 The plasma half-life is 1.2 hours, the intracellular half-life is
sekitar 3.5 hours
 Excretion is by active tubular secretion and glomerular
filtration.
 Dosis of stavudine should be reduced in patients with renal
insufficiency and low body weight.
 Batas dosis toxicity is a dose-related peripheral sensory
neuropathy. The incidence of neuropathy may be increased
when stavudine diberikan 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—terhadap kedua
zidovudine-sensitive and zidovudine-resistant HIV-1 strains
 Oral bioavailability > 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.
 Efek samping are headache, insomnia, lelah, and
gastrointestinal tidak nyaman, biasanya ringan
 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%; dosis on an empty stomach is
wajib. Cerebrospinal fluid concentrations of the drug are
sekitar 20% of serum concentrations.
 Elimination half-life is 1.5 hours, but the intracellular half-life
of the activated senyawa is as long as 20–24 hours.
 Eliminated by glomerular filtration and tubular secretion.
 Dosis toxic terkait with didanosine therapy is dose-tergantung
pancreatitis (zalcitabine and stavudine avoided)
 Efek samping termasuk nyeri 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 sekitar 25% and
increases to 39% after a high-fat meal.
 Serum half-life is 17 hours and intracellular half-life is
berkepanjangan at more than 60 hours.
 Elimination terjadi by a combination of glomerular filtration and
active tubular secretion
 Gastrointestinal keluhan (eg, nausea, diarrhea, vomiting, perut
kembung)
 The combination of tenofovir with didanosine is terkait with both
decreased virologic efficacy and increased toxicity (due to increased
didanosine levels) and therefore should be dihindari.
 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 tidak bersaing 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).
 Cukup baik diserap secara oral(45%).
 Toxicity dapat meningkat karena meningkatnya
bioavailability after a high-fat meal, efavirenz should be
minum on an empty stomach.
 Effects yang tidak diinginkan of efavirenz melibatkan the
central nervous system (pusing, drowsiness, insomnia,
headache, bingung, amnesia, agitation, delusions,
depression, mimpi buruk, euphoria); tdapat terjadi up to
50% of patients and may be parah. However, they cenderung
untuk menyelesaikan 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.
 Secara ekstensif di metabolisme oleh the CYP3A isoform to hydroxylated
metabolites and then excreted, primarily in the urine.
 Terjadi ruam sekitar 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 cenderung untuk ruam. Ruam kulit yang
mengancam jiwa jarang terjadi, including Stevens-Johnson syndrome and
toxic epidermal necrolysis.
 Nevirapine therapy should be dihentikan in patients with severe ruam
and in those with gejala konstitusional yang menyertai.
 Protease Inhibitors

 Mencegah perpisahan of the Gag-Pol polyprotein, protease inhibitors

(PIs) menghasilkan produksi yang belum matang, noninfectious viral
particles
 A syndrome of re-distribution and accumulation of body fat yang
menghasilkan in central obesity, dorsocervical fat enlargement (buffalo
hump), peripheral and facial wasting, breast enlargement, and a
cushingoid bentuk has been observed in patients receiving
antiretroviral therapy..
 Protease inhibitors have been disertai 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 jelas inhibitory effect and saquinavir
sangat sedikit.
 Lopinavir/Ritonavir

 Absorption of lopinavir is dapat ditingkatkan 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 efek samping 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
menyebabkan lopinavir metabolism.
• Interferon
 Interferon
 Interferons are host cytokines yang mengerahkan complex antiviral,
immunomodulatory, and antiproliferative activities
 Persiapan injeksi interferon alfa are available for treatment of both HBV
and HCV virus infections
 Interferon alfa-2a and interferon alfa-2b dapat diberikan subcutaneously
or intramuscularly, dimana interferon alfacon-1 is diberikan
subcutaneously. Elimination half-life is 2–5 hours for interferon alfa-2a and
-2b, tergantung pada rute pemberian.
 Efek samping khas of interferon alfa termasuk a flu-like syndrome
 Sementara hepatic enzyme elevations mungkin terjadi in the first 8–12
weeks of therapy and tampak lebih umum pada responden.
 Potensi efek yang berlawanan during chronic therapy termasuk
neurotoxicities (mood disorders, depression, somnolence, confusion,
seizures), myelosuppression, sangat lelah, weight loss, rash, cough,
myalgia, alopecia, tinnitus, gsnggusn pendengaran reversible, retinopathy,
pneumonitis, and kemungkinan cardiotoxicity.
 Interferon
 Contraindications to interferon alfa therapy termasuk
hepatic decompensation, autoimmune disease, and
jantung arrhythmia
 Alfa interferons are aborsi in primates and tidak
diberikan pada kehamilan.
 Combination therapy with NRTI agents may cause
hepatic failure (co-administration with didanosine is
not recommended)
 Co-administration with zidovudine may exacerbate
cytopenias.
• Terimakasih