A-Textbook-of-Clinical-Pharmacology-and-Therapeutics-5th-edition

INTERFERONS AND ANTIVIRAL HEPATITIS THERAPY 349
Uses
Interferon-α when combined with ribavirin (see above) provides
effective therapy for chronic hepatitis C infection
(Chapter 34). Regular interferon-α is given three times a week
(or pegylated interferon-α is given once weekly) 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-α 2a and interferon-α 2b are used to treat Kaposi’s
sarcoma in AIDS patients and interferon-α 2b is effective in
recurrent or metastatic renal cell carcinoma (Chapter 48).
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.
Adverse effects
These include:
• fever, malaise, chills – an influenza-like syndrome, and
neuropsychiatric symptoms similar to a postviral syndrome;
• lymphocytopenia and thrombocytopenia are reversible,
and tolerance may occur after a week or so;
• anorexia and weight loss;
• alopecia;
• transient loss of higher cognitive functions, confusion,
tremor and fits;
• transient hypotension or cardiac dysrhythmias;
• hypothyroidism.
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 t 1/2 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.
ADEFOVIR DIPIVOXIL
Adefovir dipivoxil is a prodrug diester of adefovir, an acyclic
phosphonate nucleotide analogue of adenosine monophosphate.
It is used in the treatment of chronic hepatitis B, especially
if interferon-α treatment has failed or is not tolerated. It
is given orally once a day until seroconversion occurs (or indefinitely
in patients with uncompensated liver disease or cirrhosis).
Adefovir dipivoxil enters cells and is de-esterified to
adefovir. Adefovir is converted by cellular kinases to its
diphosphate which is a competitive inhibitor of viral DNA
polymerase and reverse transcriptase. Hepatitis B DNA polymerase
has a higher affinity for the adefovir diphosphate than
other cellular enzymes. Adverse effects include dose-related
reversible nephrotoxicity and tubular dysfunction, gastrointestinal
upsets and headaches. It is genotoxic, nephrotoxic
and hepatotoxic at high doses. The parent compound has low
bioavailability, but the prodrug is rapidly absorbed and
hydrolysed by blood and gastro-intestinal hydrolases to yield
adefovir at 30–60% bioavailability. Adefovir is eliminated
unchanged by the kidney with a mean elimination t 1/2 of 5–7.5
hours. Dose reduction is needed in patients with renal dysfunction.
Drugs that reduce renal function or compete with
tubular secretion may increase systemic drug exposure.
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 (Chapter 46).
A number of newer oral nucleoside reverse transcriptase/
DNA polymerase inhibitors for hepatitis B are in late clinical
development.
IMMUNOGLOBULINS
For information related to immunoglobulins, see Chapter 50.
Key points
Non-HIV antiviral drugs
• Specific anti-CMV agents are ganciclovir (valganciclovir)
and foscarnet.
• Both are active against aciclovir-resistant herpes viruses.
• Ganciclovir and foscarnet are best given intravenously,
poorly or not absorbed orally, both are renally excreted.
• Valganciclovir is a prodrug ester of ganciclovir and
yields 60% bioavailable ganciclovir with oral dosing.
• Ganciclovir (bone marrow suppression) and foscarnet
(nephrotoxicity) are much more toxic than aciclovir.