ANTIVIRALS

DR.FATIMA AFTAB
PGR PHARMACOLOGY AND
THERAPEUTICS
FPGMI, SHAIKH ZAYED, LAHORE.
ANTI VIRAL AGENTS
 DRUGS FOR HERPES
 These drugs act against herpes
viruses.
 ANTI-METABOLITES
 These are prodrugs.
 Require metabolic activation by host
cells or viral enzymes.
 Analogues of nucleosides.
 Drugs include ACYCLOVIR,
GANCICLOVIR, IDOXURIDINE.
 OTHER DRUGS
 CIDOFOVIR
 FOSCARNET
 FOMIVIRSEN
 ACYCLOVIR
 Guanosine analog.
 Active against HSV-1, HSV-2 and VZV
( These have TK ).
 Activated initially by thymidine
kinase of virus.
 2nd and 3rd phosphorylations occur by
host kinases.
 ACYCLOVIR
 Acts as substrate for viral DNA
polymerase and also leads to chain
termination after incorporation into
viral DNA.
 Resistant in strains not having
thymidine kinase.
 Topical, oral and IV routes.
 Renal excretion.
 ACYCLOVIR
 USES : Oral acyclovir;
mucocutaneous and genital herpes
lesions. IV is used in severe herpes
disease; encephalitis and neonatal
HSV infection.
 Adverse effects : Oral is tolerated
well; only GI distress and headache.
IV can cause delirium, tremors,
seizures, hypotension and
nephrotoxicity.
 ACYCLOVIR
 Does not cause bone marrow
suppression. Because it requires
thymidine kinase for activation which
will only be present in virus infected
cells.
 Valacyclovir is prodrug converted to
acyclovir by hepatic metabolism.
Longer duration of action than
acyclovir.
 GANCICLOVIR
 Can use TK of HSV and VZV for step 1
of phosphorylation as well as
phosphotransferase of CMV for this
step; hence also active against CMV.
 Can also use host kinases completely
for phosphorylation.
 GANCICLOVIR
 Same MOA as Acyclovir.
 Usually given IV ( oral bioavailabilty
less than 10% ).
 Renal elimination.
 Intraocular implant can be used in
CMV retinitis.
 Valganciclovir, a prodrug of
ganciclovir; high oral bioavailability.
 GANCICLOVIR
 USES : Prophylaxis and treatment of
CMV retinitis and CMV infections in
immunocompromised individuals.
 ADVERSE EFFECTS : leukopenia,
thrombocytopenia, neutropenia
( hematotoxicity ), mucositis, hepatic
dysfunction, seizures. Severe
neutropenia can occur when used
with zidovudine or other
mylosuppressive agents.
 IDOXURIDINE
 Thymidine analog.
 Only acts against DNA viruses.
 Used topically in HSV-1 keratitis.
 Too toxic for systemic use.
 CIDOFOVIR
 It is a phosphonate.
 Activated exclusively by host cell
kinases.
 Active against HSV, CMV, Adenovirus
and HPV.
 Resistance due to mutations in DNA
Polymerase gene.
 Given IV. Undergoes renal
elimination.
 CIDOFOVIR
 Brincidofovir; prodrug. Less
nephrotoxic than cidofovir.
 USES : CMV retinitis, mucocutaneous
HSV infections ( including those
resistant to acyclovir ), genital warts.
 Major adverse effect is nephrotoxicity.
 FOSCARNET
 Directly inhibits Viral DNA and RNA
polymerase.
 Given IV.
 Renal elimination.
 USES : Alternative for CMV infections,
Acyclovir and ganciclovir-resistant
infections.
 FOSCARNET
 ADVERSE EFFECTS : Nephrotoxicity
with disturbances in electrolyte
imbalance, GI ulceration, CNS effects
( headache, hallucinations, seizures ).
 Never give with Pentamidine ( in HIV
patients with P.jiroveci infection )-
additive nephrotoxicity.
 FOMIVIRSEN
 Binds to mRNA of CMV, inhibiting
protein synthesis.
 Injected Intravitreally in CMV retinitis.
 Causes iritis, vitreitis, increased
intraocular pressure and changes in
vision.
 ANTI-HIV DRUGS
 Also called antiretroviral drugs.
 Current approach to treatment is
initiation of treatment with 3 or more
antiretrovirals. Usually include NRTIs
with protease inhibitors
 HAART ( highly active antiretroviral
therapy ) involves drug combinations.
 NRTIs
 Nucleoside reverse transcriptase
inhibitors.
 To convert RNA into DNA retroviruses
require RNA-dependent DNA
polymerase ( reverse transcriptase )
 NRTIs are prodrugs converted by host
cell kinases to triphosphates.
 MOA similar to antimetabolite
antiherpes drugs.
 NRTIs
 Resistance emergence due to
mutations in pol gene.
 Resistance usually emerges when
these are used as single agents.
 ZIDOVUDINE
 Active orally.
 Elimination is via hepatic metabolism
to glucoronides as well as renal
excretion.
 Dosage adjustment required in renal
dysfunction patients and those with
liver cirrhosis.
 Primary toxicity is bone marrow
suppression leading to anemia and
neutropenia which may req
 ZIDOVUDINE
 Gi distress,thrombocytopenia,
headaches, myalgias, acute
cholestatic hepatitis, agitation and
insomnia may also occur.
 Azole antifungals and protease
inhibitors may increase plasme
concentration of zidovudine.
 Rifampin increases clearance of
zidovudine.
 NNRTIs
 Nonnucleoside reverse transcriptase
inhibitors.
 Do not req phosphorylation to be
active.
 Directly inhibit reverse transcriptase.
 Resistance due to mutations in pol
gene.
 Nevirapine is effective in preventing
HIV vertical transmission when given
as single dose to mothers at the
 PROTEASE INHIBITORS
 Assembly of HIV virions is dependent
on an aspartate protease ( HIV-1
Protease ) encoded by pol gene.
 This enzyme cleaves precursor
polyproteins to form final structural
proteins.
 Resistance by?
 PROTEASE INHIBITORS
 They are seen to cause development
of disorders in carbohydrate and lipid
metabolism.
 Inhibition of lipid-regulatory proteins,
which have active sites with
structural homology to that of HIV
protease.
 Hyperglycemia, hyperlipidemia,
buffalo hump, gynaecomastia,
truncal obesity.
 ENTRY AND FUSION INHIBITORS
 MARAVIROC :Attaches to CCR5
receptorand blocks viral attachment.
Used orally. Substrate for
CYP3A4.Side effects include cough,
diarrhea, muscle and joint pain,
deranged LFTs.
 Enfuvirtide : Prevents fusion between
viral and cellular membranes. Given
S/C. Injection site reactions and
hypersensitivity may occur.
 INTEGRASE INHIBITORS
 Raltegravir, Dolutegravir, bictegravir,
elvitegravir.
 Bind integrase and prevent
integration of viral DNA into human
genome.
 Metabolized by glucoronidation.
 Rifampin induces UDP-
glucuronyltransferase, so increase
dose.
 Nausea, dizziness, fatigue, myopathy,
 ANTI-INFLUENZA AGENTS
 OSELTAMIVIR AND ZANAMIVIR : Inhibitors
of neuraminidases produced by influenza
A and B. Impede viral release and spread.
Oseltamiviris prodrug ( activated in the
gut and liver ). Zanamivir administered
intranasally.
 GI symptoms may occur with oseltamivir.
Zanamivir may cause cough and throat
discomfort; bronchospasm in asthmatic
patients.
 ANTI-INFLUENZA AGENTS
 AMANTADINE AND RIMANTADINE :
Prevent uncoating of influenza A
virus. Prophylactic against Influenza
A infection. Side effects include GI
irritation, ataxia, slurred speech.
Resistance to these drugs is very
high and usage of these agents has
declined.
 AGENTS USED IN VIRAL HEPATITIS
 Interferon- alpha : It is a cytokine.
Activates JAK-STAT. Activation of host
cell ribonuclease that degrades viral
mRNA.
 Renal elimination.
 Given 3 times a week.
 Pegylated forms conjugated to
polyethylene glycol can be
administered once a week.
 AGENTS USED IN VIRAL HEPATITIS
 Used in chronic HBV. Pegylated
interferon-alpha together with ribavirin in
chronic HCV. Other uses include Kaposi
sarcoma, papillomatosis, genital warts.
 LAMIVUDINE.
 ADEFOVIR DIPIVOXIL : Prodrug. Activated
to Adefovir. Competitively inhibits HBV
DNA Polymerase. Nephrotoxicity, lactic
acidosis, severe hepatomegaly may
occur.
 AGENTS USED IN VIRAL HEPATITIS
 Entecavir : Inhibits DNA polymerase.
 Ribavirin : Inhibits Replication of a
whole range of DNA and RNA viruses
including influenza A and B,
RSV,paramyxoviruses, HCV and HIV.
 NEWER DRUGS FOR HBV : Telbivudine
( inhibits HBV DNA Polymerase ),
Tenofovir ( antiretroviral drug ).
 TREATMENT OF HEP C
 Following agents are used and the
main targets are HCV-encoded
proteins that are vital to replication of
the virus.