Chemotherapeutics - Antiviral Drug Therapy

ANTIVIRAL DRUG THERAPY (EXCLUDING
ANTI-HIV DRUGS)
ANTIVIRAL DRUG THERAPY
INTRODUCTION
• Many viral illnesses are mild and/or self-limiting, but
some are deadly (e.g. the now extinct smallpox, some
strains of influenza, the global HIV-1 epidemic and
various exotic diseases, including Marburg disease).
• Some produce chronic disease (e.g. hepatitis B and C).
• Even the mild common cold is economically significant,
as is its deadly relative SARS (severe acute respiratory
syndrome).
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• Patients who are immunocompromised,
especially by HIV-1 infection, are at risk of
serious illness from viruses that are seldom
serious in healthy individuals.
• Antiviral drug therapy is therefore increasingly
important.

• Antiviral therapy is more difficult than
antibacterial therapy because viruses are
intimately incorporated in host cells and the
therapeutic targets are often similar to the
equivalent enzymes/structures in human cells.
• To summarize these problems:

I. Viral replication is intracellular, so drugs must
penetrate cells in order to be effective.
II. Viral replication usurp the metabolic
processes of host cells.
III. Although viral replication begins almost
immediately after the host cell has been
penetrated, the clinical signs and symptoms
of infection often appear after peak viral
replication is over.
• Several events in the viral life cycle may prove
susceptible as drug targets:
o when the virus is outside cells it is susceptible to
antibody attack; however, finding drugs that are non-
toxic but which can destroy viruses in this situation
remains a challenge;
o viral coat attachment to the cell surface probably
involves interaction between the virus coat and the cell
membrane surface; penetration of the cell membrane
can be prevented (e.g. for influenza A by amantadine
or neuraminidase inhibitors);
o uncoating of the virus with release of viral nucleic
acid intracellularly;
o viral nucleic acid acts as a template for new
strands of nucleic acid that in turn direct the
production of new viral components utilizing the
host cell’s synthetic mechanisms. Most non-HIV
antiviral drugs act at this stage of viral replication;
o extracellular release of new viral particles.

• Figure 45.2 summarizes the sites of action of antiviral
drugs.

NUCLEOSIDE ANALOGUES
ACICLOVIR
Uses
• Aciclovir is effective against herpes (simplex
and zoster), but is much less active against
cytomegalovirus (also a herpes virus).
• Aciclovir and its analogues have replaced
idoxuridine.
1. Aciclovir ointment (3%) accelerates healing in
herpetic keratitis.
o The efficacy of topical aciclovir in genital and labial
herpes simplex has been unimpressive.
2. Aciclovir given orally accelerates healing in
genital herpes.
o It is much less effective in secondary than in
primary infection. It does not eliminate vaginal
carriage, so Caesarean section is indicated to avoid
neonatal herpes.
3. Treatment of shingles (herpes zoster) should
be started within 72 hours of the onset and is
useful for patients with severe pain, although
it shortens the illness only modestly.
4. In generalized herpes simplex or herpetic
meningoencephalitis, aciclovir is given
intravenously.

Mechanism of action
• Aciclovir undergoes intracellular metabolic
activation to its monophosphate, selectively
in infected cells, by a specific thymidine kinase
that is coded for by the virus but not by the
host genome.
• Aciclovir monophosphate is subsequently
converted to the corresponding di- and
triphosphate (ACIC-TP).


• The viral DNA polymerase is inhibited
competitively by ACIC-TP from synthesizing
nascent/newly forming viral DNA.

Adverse effects
• These include:
1. a reversible rise in plasma urea and
creatinine;
2. neurological disturbance;
3. rash;
4. nausea and vomiting;
5. hepatitis.
Contraindications
• Aciclovir is relatively contraindicated in
pregnancy as it is an analogue of guanosine
and so potentially teratogenic in the first
trimester.

Pharmacokinetics
• Aciclovir bioavailability is approximately 20% after
administration of a standard (200 mg) dose orally, and
may be dose dependent.
• The mean elimination t1/2 of aciclovir is three hours and
it crosses the blood–brain barrier producing a CSF
concentration that is approximately 50% of that in
plasma.
• Clearance is largely renal and includes an element of
tubular secretion; renal impairment requires
dose/schedule adjustment.
Drug interactions
• Probenecid prolongs the half-life of aciclovir
by 20% by inhibiting renal tubular secretion.


FOSCARNET (TRISODIUM PHOSPHONOFORMATE)
Uses
• Foscarnet is active against several important viruses,
notably HIV-1 and all human herpes viruses, including
aciclovir resistant herpes viruses and
cytomegalovirus (CMV).
• It is used to treat CMV infections (retinitis,
pneumonitis, colitis and oesophagitis) and aciclovir-
resistant herpes simplex virus (HSV) infections in
immunocompetent and immunosuppressed hosts.
• Foscarnet is given intravenously as loading
dose followed by infusions.
• Dose reduction is required in patients with
renal failure.

Mechanism of action
• Foscarnet is a nucleotide analogue that acts
as a noncompetitive inhibitor of viral DNA
polymerase and inhibits the reverse
transcriptase from several retroviruses.
• It is inactive against eukaryotic DNA
polymerases at concentrations that inhibit
viral DNA replication.

Adverse effects
• These include the following:
o nephrotoxicity: minimized by adequate hydration and dose
reduction if the serum creatinine rises; monitoring of renal
function is mandatory;
o central nervous system effects include irritability, anxiety
and fits;
o nausea, vomiting and headache;
o thrombophlebitis;
o hypocalcaemia and hypomagnaesemia;
o hypoglycaemia (rare).
Pharmacokinetics
• Foscarnet is poorly absorbed (2–5%) after oral
administration.
• Plasma concentrations decay in a triphasic
manner and the terminal t1/2 is 18 hours.
• Foscarnet is excreted renally by glomerular
filtration and tubular excretion.
• Approximately 20% remains in the body bound
in bone.
Drug interactions
• The nephrotoxicity of foscarnet is potentiated
in the presence of other nephrotoxins, e.g.
pentamidine, gentamicin, ciclosporin and
amphotericin B.
• Administration with pentamidine can cause
marked hypocalcaemia.

GANCICLOVIR
(DIHYDROXYPROPOXYMETHYLGUANINE, DHPG)
Uses
• Ganciclovir, a guanine analogue, is used to treat
sight- or life threatening CMV infections (e.g.
retinitis, pneumonitis, colitis and oesophagitis) in
immunocompromised hosts.
• It also has potent activity against herpes viruses 1
and 2 and is used to treat aciclovir-resistant herpes.

• A loading dose is administered intravenously
followed by maintenance infusions.
• Oral ganciclovir is available for therapy
despite its poor bioavailability and is only
slightly less effective than intravenous therapy
in CMV retinitis in AIDS patients.
• It is easier for the patients and less expensive.

• Intravitreal ganciclovir implants are effective
in treating CMV retinitis and are more
effective at suppressing progression of disease
than systemic ganciclovir.
• Valganciclovir is a prodrug of ganciclovir.
• It can be used orally on a twice daily schedule
for initial control and suppression of CMV
retinitis.

Mechanism of action
• Ganciclovir is metabolized intracellularly to
its monophosphate in herpes-infected cells by
the virally encoded thymidine kinase.
• It undergoes further phosphorylation by host
kinases to its triphosphate anabolite which
competitively inhibits the CMV (or HSV) DNA
polymerase.

• If it is incorporated into nascent viral DNA, it
causes chain termination.
• Ganciclovir is concentrated ten-fold in
infected cells compared to uninfected cells.

Pharmacokinetics
• Only 4–7.5% of an oral dose of ganciclovir is
absorbed.
• Valganciclovir is well absorbed orally and is
converted to ganciclovir, yielding a ganciclovir
bioavailability of 60%.
• Ganciclovir has a mean elimination t1/2 of between
two and five hours and is virtually totally excreted
by the kidney.
• Dose reduction is needed in renal failure.
Adverse effects
• These include:
o neutropenia and bone marrow suppression
(thrombocytopenia and less often anaemia); cell
counts usually return to normal within two to five
days of discontinuing the drug;
o temporary or possibly permanent inhibition of
spermatogenesis or oogenesis;

Adverse effects
o phlebitis and pain at intravenous infusion site;
o rashes and fever;
o gastro-intestinal upsets;
o transient increases in liver enzymes and serum
creatinine in underhydrated patients.

Contraindications
• Ganciclovir is contraindicated in pregnancy (it
is teratogenic in animals) and in breast-
feeding women.

Drug interactions
• Probenecid reduces renal clearance of
ganciclovir.
• Antineoplastic drugs, co-trimoxazole and
amphotericin B increase its toxic effects on
rapidly dividing tissues including bone
marrow, skin and gut epithelium.

Drug interactions
• Zidovudine (AZT) should not be given
concomitantly with ganciclovir because of the
potentiation of bone marrow suppression.
• The pharmacology and therapeutics of other
available nucleoside analogue anti-herpes
drugs are shown in Table 45.3.


RIBAVIRIN (TRIBAVIRIN)
Uses
• Ribavirin is active against a number of RNA and
DNA (HSV-1 and HSV-2, influenza) viruses.
• It is used to treat hepatitis C (combined with
interferon) or bronchiolitis secondary to respiratory
syncytial virus infection in infants and children.
• Administration for bronchiolitis is via aerosol
inhalation.

Mechanism of action
• Ribavirin is taken up into cells and phosphorylated
to tribavirin 5-monophosphate by adenosine kinase
and is then phosphorylated to its di- and
triphosphates by other cellular kinases.
• Ribavirin-triphosphate inhibits the guanylation
reaction in the formation of the 5 cap of mRNA and
inhibits viral RNA methyltransferase.
• It has little or no effect on mammalian RNA
methyltransferase.
Pharmacokinetics
• Following nebulized administration, only small
amounts of ribavirin are absorbed
systemically.

Adverse effects
• Systemic administration can cause:
o dose-related haemolytic anaemia and
haematopoietic suppression;
o rigors (during infusion);
o rash, pruritus;
o teratogenesis.

• No systemic adverse effects of ribavirin have
been reported following administration by
aerosol or nebulizer.
• General adverse effects include:
o worsening respiration and bacterial pneumonia
(super-infection);
o pneumothorax;
o teratogenesis (a concern even with aerosol
exposure of healthcare workers).
ANTI-INFLUENZA AGENTS
AMANTADINE (OR RIMANTADINE)
• Amantadine is effective in preventing the
spread of influenza A.
• Its usefulness as an antiviral agent is limited to
influenza A.
• Its mode of action is unknown.

ANTI-INFLUENZA AGENTS
AMANTADINE (OR RIMANTADINE)
• Prophylaxis with amantadine has an
advantage over immunization in that the latter
can be ineffective when a new antigenic
variant arises in the community and spreads
too rapidly for a killed virus vaccine to be
prepared and administered.

• Prophylaxis with amantadine during an epidemic
should be considered for people at special risk (e.g.
patients with severe cardiac or lung disease, or
healthcare personnel).
• Amantadine is less effective during periods of
antigenic variation than during periods of relative
antigenic stability.
• Treating established influenza with amantadine
within the first 48 hours may ameliorate
symptoms.
• The mean elimination t1/2 is 12 hours and
elimination is via renal excretion.
• Thus, dose reductions are needed when
amantadine is given to patients with renal
failure.

Adverse effects
• These include:
• dizziness, nervousness and headaches;
• livedo reticularis.

OSELTAMIVIR PHOSPHATE
• Oseltamivir phosphate is an ethyl ester
prodrug of oseltamivir carboxylate.
• It is used to prevent and treat influenza A and
B infections, when given orally twice a day for
five days.

ZANAMIVIR
• This is another inhibitor of influenza virus
neuraminidase enzymes.
• If given early during influenza A or B infection
via intranasal route it is effective in reducing
symptoms.

INTERFERONS AND ANTIVIRAL HEPATITIS THERAPY
• Interferons are cytokines (mediators of cell growth and
function).
• They are glycoproteins secreted by cells infected with
viruses or foreign double-stranded DNA.
• They are nonantigenic and are active against a wide
range of viruses, but unfortunately they are relatively
species specific.
• Thus, it is necessary to produce human interferon to
act on human cells.
• Interferon production is triggered not only by
viruses but also by tumour cells or previously
encountered foreign antigens.
• Interferons are important in immune
regulation.
• Four main types of interferon are recognized:

1. Interferon-α – known previously as leukocyte
or lymphoblastoid interferon.
2. interferon-β from fibroblasts;
3. interferon-ω has 60% homology with
interferon-α;
4. interferon-γ formerly called ‘immune’
interferon because it is produced by
lymphocytes in response to antigens and
mitogens.
• Commercial production of interferon by
cloning of human interferon genes into
bacterial and yeast plasmids is now available,
facilitating large-scale production.

Uses
• Interferon-α when combined with ribavirin provides
effective therapy for chronic hepatitis C infection.
• Regular interferon-α is given three times a week by
subcutaneous injection, for 6–12 months.
• Interferon-β is of some benefit in patients with
relapsing multiple sclerosis.
• Interferon-α is used to treat condylomata acuminata
by intralesional injection.

• All three interferons are used to treat hairy cell
leukaemia.
• Interferon-α2a and interferon-α2b are used to treat
Kaposi’s sarcoma in AIDS patients and interferon-α2b is
effective in recurrent or metastatic renal cell carcinoma.
• Recombinant interferon-γ has been used for the
treatment of chronic granulomatous disease.
• Interferon therapy is also beneficial in chronic
myelogenous leukaemia, multiple myeloma, refractory
lymphoma and metastatic melanoma.

Mechanism of action
• Interferons bind to a common cell-membrane
receptor, except interferon-γ, which binds to
its own receptor.

• Following receptor binding, interferons activate
the JAK-STAT signal transduction cascade and lead
to nuclear translocation of a cellular protein
complex that binds to genes containing IFN-specific
response elements and stimulating synthesis of
enzymes with antiviral activity, namely 25-
oligoadenylate synthetase (which activates
ribonuclease L, which preferentially cuts viral RNA);
a protein kinase activity (important in apoptosis)
and a phosphodiesterase that cleaves tRNA.
• The onset of these effects takes several hours, but
may then persist for days even after plasma
interferon concentrations become undetectable.
• Interferon also increases the presentation of viral
antigens in infected cells and upregulates
macrophage activation and T cell and natural killer
cell cytotoxicity, thereby increasing viral elimination.
• The interferon concentrations needed to produce
antiviral effects are lower than those required for
their antiproliferative effects.
Pharmacokinetics
• Most clinical experience has been gained with
interferon-α, administered subcutaneously.
• Following subcutaneous administration, peak plasma
concentrations occur at between four and eight hours
and decline over one to two days.
• The mean elimination t1/2 is three to five hours.
• Polyethylene glycol (PEG)-conjugated (PEG-ylated)
interferons are now used clinically, have protracted
half-lives and may be administered weekly.
• Elimination of interferons is complex.
• Inactivation occurs in the liver, lung and
kidney, but interferons are also excreted in the
urine.

LAMIVUDINE (3-THIACYTIDINE)
• Lamivudine is a nucleoside analogue reverse
transcriptase/DNA polymerase inhibitor.
• It is used as chronic oral therapy for hepatitis B
and HIV.
• Oral administration twice daily is well tolerated
in hepatitis B patients and the most common
adverse effects are worsening hepatic
transaminases during and after therapy.


END

Chemotherapeutics - Antiviral Drug Therapy

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ANTIVIRAL DRUG THERAPY (EXCLUDING

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