Anti-viral agents.antiviral drugs by dr fahad

 DNA viuses/disease RNA viruses/disease
 Small pox Poliomyelitis
 Chicken pox Measles
 Herpes simplex(HSV) Mumps
 Varicella zoster(VZV) Rabies
 Hepatitis-B(HBV) Influenza
 Cytomegalovirus HIV

 Viruses can replicate only inside the host
cell and also utilize the host enzyme system.
 Due to this reason targeting the virus is vey
difficult and so usually the anti-viral drugs
produce severe toxic effects.

 free viral particles
 attachment to the host cell
 penetration
 uncoating
 replication
 Assembly and maturation
 Release of virion

 Drugs used against herpetic infections(anti-herpetic):
 Acyclovir , valacyclovir, famciclovir, penciclovir, ganciclovir,
foscarnet, idoxoridine.
 Drugs used against HIV infection(antiretroviral):
 Nucleoside reverse transcriptase inhibitors:
zidovudine, stavudine,lamivudine,didanosine,
zalcitabine & abacavir.
 Non-nucleosidereverse transcriptase inhibitors:
navirapine, dilavirdine & efavirenz.
 Protease inhibitors:
saquinvir,indinavir,ritonavir, lopinavir & nelfinavir.
 Fusion inhibitor:
enfuridine .

 Ai- influenza agents:
amantadine, rimantadine, oseltmavir.
 Other antiviral agents:
interferone ribvarin .

 Acyclovir :
It is a prodrug.
It is a synthetic drug being the analogue of purine
nucleoside that has anti-herpetic activity, mainly
effective against HSV1 & HSV2, less effective
against Varicella zoster virus(VZV).

Acyclovir
HSV
thymidine kinase
Acyclovir Monophosphate
cellular
enzymes
Acyclovir diphosphate
cellular
enzymes
Acyclovir triphosphate
“ Inhibits DNA synthesis & viral
replication”

 It selectively binds to the cell that are infected with the herpetic
infections. Inside the cells they are converted to the acyclovir tri-
phosphate. Triphosphate in turn inhibits the Viral DNA synthesis.
 Pharmacokinetics
 Available for oral, topical & I/V administration.
 Highly potent antiherpetic drug.
 Has high therapeutic index ( safe drug), with very little toxicity to
the host cells.
 Orally has very little bioavailability, poorly bound to the plasm
proteins, widely distributed in the body, can freely cross the BBB,
excreted in urine.

 Genital herpes: effective against genital HSV
infections.
 Herpetic encephalitis: I/V acyclovir is recommended
for HSV causing encephalitis.
 Herpes simplex keratitis: Acyclovir is used topically
for the treatment of herpetic keratoconjunctivitis.
 Mucocutaneous HSV: Acyclovir is effective in the
treatment of mucocutaneous HSV in immunocompromised
patients.
 Herpetic whitlow(nail bed infection): oral
acyclovir is useful this.
 Chicken pox & herpes zoster: oral acyclovir is used
which reduces the duration of illness.

 Mild side effects. Usually nausea, vomiting ,
diarrhea.
 Since it can freely cross the BBB so can at
time produce confusion in mild doses but in
high doses may cause neurotoxicity with
tremors, disorientation & convulsions.
 Topical preparations may cause irritation,
burning & itching.

 Valacyclovir is the pro-drug of Acyclovir. It is
converted to acyclovir in the liver.
 Famiciclovir is prodrug of penciclovir.
Famiciclovir is taken orally , well absorbed &
converted to penciclovir. The mechanism of
action of valacyclovir & Famiciclovir is the
same as that of acyclovir.
Acyclovir
Intracellular
activation to
acyclovir
triphosphate
Valacyclov
ir
(prodrug)
Famciclovir
(prodrug)
Penciclovir
Intracellular
activatation to
penciclovir
triphosphate
Inhibit viral DNA
synthesis of HSV-1,
HSV-2, VZV&
Hepatitis B virus.

 Mechanism
 Inorganic pyrophosphate analog inhibits viral DNA
polymerase, RNA polymerase, and HIVreverse
transcriptase directly without requiring activation by
phosphorylation
 Blocks the pyrophosphate binding site of these
enzymes
 Inhibits cleavage of pyrophosphate from
deoxynucleotide triphosphates.
 Spectrum
 HSV, VZV, CMV, EBV, HHV-6, HHV-8, and HIV-1.
 Phamacokinetics
 i.v. only cos of poor oral bio & GI intolerance to oral

 Indications
 CMV retinitis (intravitreally), CMV colitis, CMV
esophagitis, acyclovir-resistant HSV infection, and
acyclovir-resistant VZV infection
 + GCV ~ synergistic (ADR’s too)
 ADR
 Renal impairment ~ hypo- or hypercalcemia, hypo-
or hyperphosphatemia, hypokalemia, and
hypomagnesemia (Pentamidine)
 CNS ~ headache, hallucinations, and seizures
(Imipenem)

 Competitive inhibition of thymidylic acid
synthase → block DNA synthesis ~ No effect
on RNA virus.
 Only topical application because of its
greater side effects in systemic application.
 Treatment of ocular or dermal infections due
to herpesvirus or cowpox virus, especially
acute epithelial keratitis due to herpesvirus.

 Amantadine , Rimantadine, Oseltamivir.
 Amantidine : it is an anti-viral drug also used as an
antiparkinsonian drug.
 It inhibits the replication of influenza –A virus and so
prevents the viral replication.
 It is administered orally, well absorbed from GI tract and
excredted unchanged in urine.
 Uses:
 for the prophylaxis & treatment of influenza-A viral infection
 for the treatment of parkinsonism
Adverse effects: anorexia, nausea, vomiting, epigastric
distress, headache, insomnia, confusion, hallucinations &
hypotension. Contraindicated in pregnancy as it is
teratogenic.

 Rimantidine : mechanism of action is the same
as that of amantidine, but has a longer duration
of action.
 Oseltamivir : it selectively inhibits influenza-
A(bird flu) & influenza-B viruses
neuroaminidases. It is used orally for both the
influenzea.

 These drugs enter the HIV infected cells where they
are acted upon by the cellular kinase enzymes and
are converted to their triphosphate forms.
 These triphospates then inhibit the reverse
transcriptase enzyme of the virus .

 They also incorporate into the growing viral DNA and
cause premature chain termination of the DNA and
inhibit DNA synthesis.

 NRTI’s include
 zidovudine,
stavudine,lamivudine,didanosine,zalcitabine &
abacavir
 Zidovudin: it is the prototype drug of NRTIs, the first
anti-retroviral drug.
 Effective against HIV-1 & HIV-2.
 It also protect the cells that are not infected.
 Can cross BBB & placenta.
 Taken orally, well absorbed from GI tract. Metabolized by
glucoronoid conjugation and excreted in urine.

 common adverse effects:
 Bone marrow suppression, anaemia & nutropenia.
 Nausea ,vomiting, abdominal discomfort, headache &
insomnia are commonly seen in the initial stages of
the therapy.
 Long term therapy adverse effects:
 Hepatomegaly,myopathy with fatigue & lactic
acidosis.
 Precautions
 Before zidovudine therapy blood complete &
creatine kinase should be monitored .

 Drug interactions of Zidovudine:
 Zidovudine + paracetamol:
Both are metabolized by glucoronide conjugation .
Paracetamol competes and interferes with the
glucoronide conjugation of Zidovudine and thus
increases the plasma concentration of zidovudine
leading to toxicity.
 Azoles + zidovudine:
Azoles inhibit the liver herpetic microsomal enzyme
system causing an increase in the blood levels of
Zidovudine.
 Zidovudine + stavudine:
They should not be given together as they compete for
intracellular phosphorylation.

 Didanosine, stavudine, zalcitabine &
lamivudine.
 Orally effective . The adversities are peripheral
neuritis , pancreatitis, GI disturbances, lactic
acidosis, skin rashes etc.

(HAART) Highly Active Antiretroviral Therapy.
Didanosine, Stavudine, Zalcitabine, Lamivudine
Transported into cells and activated to respective
triphosphate forms
inhibit HIV reverse transcriptase
DNA (chain termination)

 Nevirapine , delavirdine, efavirenz
binds directly to reverse transcriptase
enzyme & inhibit their function

 Effective against HIV-1.
 Has no effect against HIV-2.
 There is no cross resistance with NRTI’s.
 Both NNRTI’s & NRTI’s are given together for
the treatment of AIDS.

 Indinavir, Nelfinavir, Ritnavir.
 Protease inhibitors (PI’s) competitively inhibit
HIV protease enzyme preventing the assembly
and maturation of virus before they are released
from the infected cells. These unassembled
viral particles are non-infectious.

 Among the (PI’s) there is cross –resistance , but there
is no cross –resistance b/w PI’s & NRTI’S. They are
usually given together for the treatment of AIDS.
 They are poorly absorbed from the GI tract &
extensively metabolized in the liver.
 They are redistributed and accumulate in the fat in
the back and abdominal regions. They also produce
skeletal muscle wasting, hyperlipedimia, insulin
resistance.

 ENFUVIRTIDE:
This blocks the entry of HIV into the cells by preventing the
fusion of virus with the cellular membrane.
It also improves the CD4 count.
It decreases the viral titer especially when used with other
antiretroviral drugs.
Usually very effective when given with PI’S or RTI’S.
It is always administered s/c.
Enfuvirtide causes severe pain at the site of infection, not only
this it also may lead to lymphadenopathy & allergic reactions.

 Interferons:
These are actually the proteins derived from the
virus infected cells.
There are three major types of interferons.
α interfrone, β interferon, γ interferon.

Anti-viral activity of interferon is due to
Inhibition of viral penetration
Inhibition of uncoating of virus inside the
host cell.
Inhibition of synthesis of mRNA.
Inhibition of translation of viral proteins
Inhibition of assembly of viral particles and
their release.

 They are administered orally , S/C, I/M as
well directly into the lesions.
 Indications
 Interferon-α for
 hairy cell leukemia
 venereal warts
 herpetic infections
 chronic hepatitis B & C
 Kaposi’s sarcoma in HIV patients.

 It is a synthetic purine nucleoside analogue.
 Ribavirin monophosphate competitively
inhibits the cellular enzymes required for the
synthesis of guanosine triphosphate(GTP) and
the nucleic acids.
 Ribavirin triphosphate also inhibits mRNA
synthesis.
 It is given orally, aerosal and i.v. route.

 It is effective against RNA & DNA viral
infections.
 Aerosal or i.v. ribavirin is used to treat
 Severe influenza
 Parainfluenza
 Measles
 Adenovirus
 Respiratory syncytial infections
 Hepatitis B

 Nausea
 Vomiting
 Tirdness
 Cough
 Dyspnoea
 Anemia
 Insomnia
 Respiratory & conjunctival irritation due to aerosal therapy.
 Contraindicated in pregnancy as it is teratogenic, mutagenic,
embryotoxic & gonadotoxic.

 ANTI-RETROVIRAL DRUGS
Entry or fusion inhibitor - reverse transcriptase inhibitors- PI’s
 NRTI’s NNRTI’S
 Zidovudine Nevirapine
 Stavudine Delaverdine
 Didanosine Efavirenz
 Zalcitabine
 Lamivudine

 All the retroviruses contain RNA-dependent DNA-
polymerase ( reverse transcriptase) enzyme.
 These viruses decrease CD4 (immune cells)
causing profound depletion of cell mediated
immunity.
 So the infected person is prone to opportunistic
infections like Kaposi’s sarcoma & lymphoid
malignancies.

 ELISA(enzyme linked immunosorbent assay):
 This is a screening test for the presense of HIV antibodies.
 Western blot test:
 HIV- positive cases are confirmed by this
test.it detects the presence of antibodies.

 To suppress HIV replication & improve the
immune status of the person
 To prevent the emergence of drug resistant
virus
 To prevent & treat the opprtunistic
infections.

 HAART regimen is followed in order to
achieve the objectives
 Monotherapy is no longer recommended
 In HAART regimen drugs with diffent
mechanism of actions are used. Usually these
are given in combinations in order to have
synergistic effects.
 2NRTI’S+ 1NNRTI
 2NRTI’S+ 1PI

 Treatment should be started in
 all the symptomatic cases----irrespective of
CD4 cell count or HIV-RNA levels.
 Asymptomatic cases with CD4 cell count< 200
per cubic milliliter & plasma HIV-RNA load more than
20,000/ml.

 Monitoring therapy
 By estimating the leve;l of HIV – RNA load &
CD4.
 Prophylaxis of HIV infection (post-
exposure prophylaxis):
 Doctors, nurses , technicians & other health
workers who have had accidental exposure to
HIV infection with the surgical instruments,
blood transfusion or needle – prick injury require
prophylactic therapy with Zidovudine,
lamivudine & even indinavir or nelfinavir. In HIV
– positive pregnant women , zidovudine should
be given to the baby for 6 months

 Doctors, nurses , technicians & other
health workers who have had accidental
exposure to HIV infection with the
surgical instruments, blood transfusion or
needle – prick injury require prophylactic
therapy with Zidovudine, lamivudine &
even indinavir or nelfinavir. In HIV –
positive pregnant women , zidovudine
should be given to the baby for 6 weeks.

Anti-viral agents.antiviral drugs by dr fahad

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