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

A N G G E L I A P , M D . P H A R M AC O LO GY A N D
T H E R A P E U T I C D E P T.

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 1520% 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 2.53.3 hours.

ANTIHERPETIC AGENT

FAMCICLOVIR

Famciclovir is the diacetyl ester prodrug of 6deoxypenciclovir, 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 37 hours.

eliminated primarily by renal excretion following glucuronidation in the liver

The most common adverse effect of zidovudine is myelosuppression,

resulting in macrocytic anemia (14%) or neutropenia (28%).

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 fooddependent

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 neuropathyinducing drugs such as didanosine and zalcitabine.

LAMIVUDINE (3TC)

Cytosine analog

Synergistic with a variety of antiretroviral nucleoside analogs

including zidovudine and stavudineagainst both zidovudinesensitive 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 3040%; 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 2024 hours.

Eliminated by glomerular filtration and tubular secretion.

The major clinical toxicity associated with didanosine therapy is dosedependent 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 (4055 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 fooddependent. The drug is highly lipophilic and achieves cerebrospinal fluid
levels that are 45% of those in plasma.

Serum half-life is 2530 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 46

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 25 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 812 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.

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