Obat antivirus

Virus??
Parasit intraseluler obligat, dimana virus
tersebut memanfaatkan :
enzim-enzim metabolik dari sel inang
ribosom inang untuk sintesis protein

Kehidupannya sangat tergantung pada sel

inang. Tak ada yang dapat dibuatnya tanpa sel
inang

Struktur virus
Partikel virus (virion) terdiri dari
bagian-bagian berikut:
inti asam nukleat: DNA or RNA
sering terdapat enzim spesifik
virus
ditutupi oleh protein : capsid
kadang-kadang terdapat lipid
pada lapisan terluar
envelope

Klasifikasi virus
RNA Viruses

DNA viruses

Contain an DNA genome.

Contain an RNA genome.

Virus replication:
DNA polymerase

Examples:
Herpes Virus
Hepatitis B virus
Epstein-Barr virus

Virus replication:
RNA-dependent RNA polymerase
Reverse transcriptase

(Retroviruses)

Examples:
Rubella virus
Dengue fever virusHepatitis A

virus
Hepatitis C virus
HIV
Influenza virus

Siklus hidup
1.Attachment

: melekatnya virus pada reseptor yang

terdapat pada permukaan sel inang;

2.Entry

: masuknya virus melewati membran sel inang;

3.Uncoating

: uncoating asam nukleat virus;

4.Replication

sintesis protein pengatur awal ( cth, asam nukleat polimerase;

sintesis virus baru RNA or DNA;
sintesis protein pembentuk struktur;
5. Assembly (maturation) : pematangan partikel virus;
6. Release : pelepasan dari sel

3
4
5

Poin penting

Banyak virus menginfeksi sel inang spesifik

Banyak infeksi virus bersifat self limiting,

tidak memerlukan pengobatan ; cth common
cold yang disebabkan oleh rinovirus.

Infeksi virus yang umum seperti influenza,

chicken pox, mumps biasanya dapat diatasi
oleh sistem imun tubuh.

Virus

lain dapat menyebabkan penyakit

serius dan fatal sehingga memerlukan
pengobatan yang agresif ; cth HIV (AIDS)

Virus Groups of Clinical Importance

Virus Genera

Nucleic Acid

Clinical Illness

Adenovirus

DNA

URTIs, Eye infections

Hepadnaviridae

DNA

Hepatitis B, Cancer (?)

Herpesvirus

DNA

Genital herpes, Varicella, Encephalitis, Retinitis

Papillomavirus

DNA

Papilloma, Cancer

Parvovirus

DNA

Erythema infectiosum

Arenavirus

RNA

Lymphocytic choriomeningitis

Bunyavirus

RNA

Encephalitis

Coronavirus

RNA

URTIs

Influenzavirus

RNA

Influenza

Paramyxovirus

RNA

Measles, URTIs

Picornavirus

RNA

Poliomyelitis, diarrhea, URTIs

Retrovirus

RNA

Leukemia, AIDS

Rhabdovirus

RNA

Rabies

Togavirus

RNA

Rubella, Yellow fever

Obat anti virus

Vaksin sering digunakan untuk membangun

sistem kekebalan sebelum infeksi virus
terjadi.

Agar efektif, antivirus harus dapat

menghambat entry atau keluarya virus ke sel
inang atau aktif di dalam sel inang

Tantangan terapi anti virus.

replikasi virus yang cepat menyebabkan
sulitnya mengembangkan anti virus yang
efektif
Virus dapat bermutasi dengan cepat : obat
menjadi tidak efektif
Kesulitan obat menemukan virus tanpa
mengganggu sel normal inang

10

ANTI-HERPES/ ANTI VZV

HSV = herpes simplex virus
VZV = Varicella Zoster virus

ACYCLOVIR
Aktif

terhadap HSV1, HSV2, & VZV

Aktifitas lebih lemah terhadap EBV
(ebstein bar virus), CMV (cytomegalo
virus)

Mekanisme kerja:
Tiga

tahap fosforilasi

Farmakokinetik
BA oral

10-30%, menurun dengan peningkatan

dosis
BA relatif meningkat sampai 70% setelah
pemberian valasiklovir
Terdistribusi luas pada cairan tubuh termasuk
cairan vesikuler dan CSF
Terkonsentrasi di ASI, cairan amnionik dan
plasenta
Absorbsi perkutan rendah

Penggunaan dalam terapi:

Herpes

genital (awal dan kambuhan) :

200 mg 5x/hari selama 10 hari oral

5 mg/kg per 8 jam IV
Recurrent: 400 mg 2x/hari atau 200 mg

3x/hari

THERAPEUTIC USES:
ACUTE

HERPES ZOSTER (SHINGLES)

SYSTEMIC ACYCLOVIR PROPHYLAXIS
HSV ENCEPHALITIS
VARICELLA ZOSTER VIRUS INFECTION
CMV PROPHYLAXIS

Efek samping:
Sediaan

topikal-iritasi mukosa dan rasa

terbakar pada luka genital
ORAL mual, diare, rash, sakit kepala,
insufisiensi ginjal, neurotoksisitas
IV- insufisiensi ginjal, CNS

PENCICLOVIR
Aktivitas

dan potensi mirid dengan

asiklovir terhadap HSV & VZV
Aktif terhadap HBV (hepatiis B virus)

MK:
Menghambat

sintesis DNA virus

Awalnya difosforilasi oleh viral thymidine
kinase
Penciclovir trifosfat merupakan inhibitor
kompetitif terhadap viral DNA polymerase
Potensi 100 lebih rendah dibanding asiklovir
tapi berada pada konsentrasi yg lebih tinggi
dan lebih lama dalam sel yang terinfeksi

Penggunaan dalam terapi:

dosis

5 mg/kg per 8-12 jam iv selama 7

hari seara dengan asiklovir utk infeksi
mucocutaneous HSV
Sediaan Topical 1% penciclovir cream
dioleskan tiap 2 jam, 4 hari utk labial
HSV

Efek samping:
Mutagenik

pada konsentrasi tinggi

IO yang signifikan secara klinis tidak
teridentifikasi

ANTIVIRAL DRUGS DNA & RNA VIRUSES

DRUG

Acylovir

MECHANISM/
VIRAL
SELECTIVITY
Metabolized by
thymidine kinase
to triphosphate

Pencyclovir

CLINICAL
USE
Herpes
simplex 1 &
2, varicella
zoster

VIRAL
RESISTANCE
Produce
abnormal
thymidine kinase

UNDESIRABLE
SIDE EFFECTS
Skin irritation,
burning,
crystalline
nephropathy

Oral HSV
(coldsores)

Valacyclovir

L-valyl ester of
acyclovir
converted to
acyclovir

Herpes zoster
(shingles)

Idoxuridine

Phosphorylated
metabolite
incorporates into
DNA causing
strand breaks

Herpes
simplex
keratitis. No
effect on RNA
viruses

Famciclovir

Phosphorylated by
viral thymidine
kinase to
penciclovir
triiphosphate

Shortens
duration of
herpes zoster
& genital
herpes

Ganciclovir

Metabolized by
thymidine kinase
to triphosphate .
Preferentially
phosphorylated to
active drug in
CMV infected cells

CMV retinitis
& severe
systemic CMV
infections

PHARMACOKINETIC
S

NOTES

IV/PO. Administer
slowly. CNS level=50%
serum level. Decrease
dose w/ kidney
dysfunction
Topical

Resistance
develops

Some resistant
strains lack
thymidine
kinase. Cannot
activate drug.

Nausea, headache

PO. Slightly better oral

absorption than
acyclovir

No clear
advantage
over acyclovir

Photophobia,
irritation of
conjunctiva &
eyelid

Eyedrops

Drug is a
halogenated
derivative of
deoxyuridine

Minimal toxicity.
Headache

PO. Decrease dose

with renal dysfunction.

Granulocytopenia,
thrombocytopenia

IV/PO. Excreted
unchanged in urine.
Decrease dose with
renal dysfunction.

Do not
coadminister
zidovudine
(granulocyto
penia) or
imipenemcilastatin
(seizures)

Cidofovir

Metabolized to
diphosphate
form. Otherwise
like ganciclovir.

CMV retinitis

Foscarnet

Analog of
pyrophosphate.
Competes for
pyrophosphate
site in viral but
not human, DNA
polymerase &
reverse
transcriptase

CMV retinitis

Amantadine

Prevents virus
from entering
susceptible cells

Rimantadine

Ribavirin

Nephrotoxicity
may be reduced
by hydration &
coadministration
of Probenicid.
Neutropenia.

Does not need

phosphorylation,
it is active
against
thymidine kinase
deficient strains

Renal toxicity,
seizures,
hypocalcemia,
fever, anemia,
diarrhea, nausea

IV. >80% excreted

unchanged in the
urine. CSF
penetration
variable. Reduce
dose with renal
dysfunction.

Treatment &
prophylaxis of
influenza A

Depression, CNS
toxicity, CHF,
orthostatic
hypotension,
urinary retention

PO. Excreted
unmetabolized.

Analog of
amantadine ,
inhibits viral
uncoating

Prophylaxis in
children

Fewer CNS side

effects, risk of
seizure

PO. Prolonged
elimination w/
renal or hepatic
dysfunction

Unknown
mechanism

RSV

Decreased
pulmonary
function.

Aerosol
administration.
Absorbed
systemically.

Deposited in bone
& teeth. Hydrate
patient during
therapy to protect
the kidney

May precipitate in
ventilator tubing.

ANTI-INFLUENZA

AMANTADIN/RIMANTADIN
Menghambat

proses uncoating virus RNA

influenza A di dalam cell inang, mencegah
replikasi
Efektif menurunkan durasi gejala influenza
jika diberikan dalam 48 jam setelah onset

FK
Absorpsi

oral baik
Ekskresi dalam bentuk tak termetabolisme
di urin
Amantadin dapat diekskresikan lewat ASI

Efek samping
Umum

: gangguan GI dan CNS minor

(gugup, light headanche, susah konsentrasi,
insomnia, mual, nafsu makan berkurang)
Amantadin konsentrasi tinggi di plasma :
reaksi neurotoksik serius : delirium, kejang,
koma, aritmia

Penggunaan terapi
Pencegahan

dan pengobatan influenza A

200 mg/hari dalam 1 atau 2 dosis
(pengobatan)
Pencegahan : harus dimulai ketika mulai
teridentifikasi pandemi virus 100mg/hari (4
8 minggu)

ZANAMIVIR/OSELTAMIVIR
Penghambat

Neuroaminidase
Menghambat replikasi influenza A & B

FK
Diserap

dengan cepat setelah pemberian

oral (BA 80%)
Eliminasi di ginjal dalam bentuk tak
berubah
Berinterkasi dengan probenecid
(meningkatkan T1/2 2x)

Efek samping
Mual,

rasa tak nyaman di lambung, muntah,

lokal iritasi
Konsentrasi yang sangat tinggi berhungan
dengan kematian (tikus)

ANTI-HEPATITIS

ADEFOVIR
Secara

kompetitif menghambat HBV

DNA polymerase
Menghambat sintesis DNA
Efek samping : nefrotoksik, pusing,
diare, ganggian abdomen)
Pengobaan infeksi HBV kronis 10 mg/hari

INTERFERON
Protein

endogen yang dihasilkan dan dilepaskan

oleh sel sebagai respon terhadap patogen
Menginduksi enzim, menekan proliferasi, aktivitas
imunomodulator dan menghambat replikasi virus
Menghambat penetrasi dan & uncoating
Untuk pengobatan HBV & HCV

ANTIRETROVIRAL
AGENTS

CURRENT ARV MEDICATIONS

NRTI

PI

Abacavir
Didanosine
Emtricitabine
Lamivudine
Stavudine
Tenofovir
Zidovudine

Atazanavir
Darunavir
Fosamprenavir
Indinavir
Lopinavir
Nelfinavir
Ritonavir
Saquinavir
Tipranavir
Fusion Inhibitor

NNRTI
Efavirenz
Etravirine
Nevirapine

Enfuvirtide

Fixed-dose Combinations
Zidovudine/ lamivudine
Zidovudine/lamivudine/abacavir
Abacavir/lamivudine
Emtricitabine/tenofovir
Efavirenz/emtricitabine
/tenofovir

ANTIVIRAL DRUGS - RETROVIRUSES

DRUG

MECHANISM &
VIRAL SELECTIVITY

CLINICAL
USE

VIRAL
RESISTANCE

Zidovudine
(AZT)

Thymidine analog is
incorporated into DNA
of human
immunodeficiency
viirus causing
termination of the viral
DNA chain

HIV.
Prevention
of maternalfetal
transmissio
n of HIV

Mutations in
reverse
transcriptase

Didanosine
(ddl)
Zalcitabine
(ddC)
Lamivudine

-Metabolized
intracellularly to
dideoxynucleotide
triphosphate that
inhibits reverse
transcriptase &
incorporates into viral
DNA.
-Nucleotides fail to bind
to ddATP bec it lacks
free 3 OH group

HIV

Mutations in
reverse
transcriptase

Stavudine

Metabolized to
stavudine triphosphate
w/c inhibits HIV
reverse transcriptase &
DNA polymerase.

HIV

UNDESIRABLE
SIDE EFFECTS

PHARMACO
KINETICS

NOTES

Headaches,
nausea, myalgias,
anemia,
neutropenia,
macrocytosis

PO. Well
absorbed,
rapidly
metabolized
by liver

Acetamino
phen
increases
risk of
hematologi
c toxicity

Peripheral
neuropathy,
pancreatitis,
diarrhea,
headache,
insomnia,
vomiting, nausea,
rash, abdominal
pain

IV/PO.
Partially
metabolized in
liver, excreted
in the urine.
Toxicity may
be enhanced
by renal or
hepatic
dysfunction.

Limited
utility as a
single
agent
therapy
because of
viral
resistance

Peripheral
neuropathy

PO

Not
indicated
for initial
monothera
py of HIV

Ritonavir
Indinavir
Saquinavir
Nelfinavir

Inhibts HIV protease .

Results in immature
virion

HIV

Mutations in
protease
sequence
reduce
affinity of
protease
inhibitors

GI distress,
headache,
neurologic
symptoms.
Indinavir
associated w/
increase risk
for kidney
stones

PO.
Metabolized
by P450 in
liver. Reduce
dose in
patients with
liver disease.
Poor CNS
penetration

Potentially
serious
drug
interaction
s due to
P450
competitio
n

Nevirapine
Delavirdene

Nob-nucleoside
inhibitor of HIV reverse
transcriptase

HIV. Never
as
monothera
py due to
rapid
developme
nt of
resistance

Rapid
resistance
develops
due to
mutations in
reverse
transcriptas
e

Severe skin
rash, fever,
nausea,
headache

PO. Well
absorbed.
Nevirapine
crosses
placenta &
has better
CNS
penetration
than
Delavirdene

Delavirde
ne failed
to show
clinical
efficacy
when
added to
didanosin
e in
clinical
trial