DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

Antiviral Agents (Nonretroviral)
Edward P. Acosta
and Charles Flexner
Most antivirals currently available in the U.S. have been
developed and approved in the last two decades. This
flurry of activity was driven by successes in rational
drug design and approval that began with the anti-herpesvirus
nucleoside analog acyclovir, whose discovery
and development resulted in the awarding of a Nobel
Prize to Gertrude Elion and George Hitchings in 1988.
Because viruses are obligatory intracellular microorganisms
and rely on host biosynthetic machinery to
reproduce, there were doubts about the possibility of
developing antiviral drugs with selective toxicity, but
those doubts have long been erased. Viruses are now
obvious targets for effective antimicrobial chemotherapy,
and it is certain that the number of available agents
in this category will continue to increase.
Viruses are simple microorganisms that consist of
either double- or single-stranded DNA or RNA
enclosed in a protein coat called a capsid. Some viruses
also possess a lipid envelope derived from the infected
host cell, which, like the capsid, may contain antigenic
glycoproteins. There are distinct stages of viral replication
and the classes of antiviral agents that can act at
each stage (Table 58–1). Effective antiviral agents
inhibit virus-specific replicative events or preferentially
inhibit virus-directed rather than host cell–directed
nucleic acid or protein synthesis. Host cell molecules
that are essential to viral replication also offer targets
for intervention. Some effective antiviral agents (e.g.,
interferons; see Chapter 35) have multiple mechanisms
of action that include modulation of host immune
responses. Figure 58–1 gives a schematic diagram of
the replicative cycle of typical DNA and RNA viruses.
DNA viruses (and the diseases they cause) include
poxviruses (smallpox), herpesviruses (chickenpox,
shingles, oral and genital herpes), adenoviruses (conjunctivitis,
sore throat), hepadnaviruses (hepatitis B
[HBV]), and papillomaviruses (warts). Most DNA
viruses enter the host cell nucleus, where the viral DNA
is transcribed into mRNA by host cell polymerase;
mRNA is translated in the usual host cell fashion into
virus-specific proteins. An exception to this strategy are
poxviruses, which carry their own RNA polymerase
and replicate in the host cell cytoplasm.
For RNA viruses, the replication strategy relies
either on enzymes in the virion to synthesize mRNA or
has the viral RNA serving as its own mRNA. The
mRNA is translated into various viral proteins, including
RNA polymerase, which directs the synthesis of
more viral mRNA and genomic RNA (Figure 58–1B).
Most RNA viruses complete their replication in the
cytoplasm, but some, such as influenza, are transcribed
in the host cell nucleus. Examples of RNA viruses (and
the diseases they cause) include rubella virus (German
measles), rhabdoviruses (rabies), picornaviruses
(poliomyelitis, meningitis, colds, hepatitis A), arenaviruses
(meningitis, Lassa fever), flaviviruses (West
Nile meningoencephalitis, yellow fever, hepatitis C),
orthomyxoviruses (influenza), paramyxoviruses
(measles, mumps), and coronaviruses (colds, severe
acute respiratory syndrome [SARS]). Retroviruses are
a special group of RNA viruses that include human
immunodeficiency virus (HIV); chemotherapy for retroviruses
is described in Chapter 59.
Table 58–2 summarizes currently approved drugs
for nonretroviral infections. Their pharmacological
properties are presented below, class by class, as listed
in the table.
ANTI-HERPESVIRUS AGENTS
Infection with herpes simplex virus type 1 (HSV-1) typically
causes diseases of the mouth, face, skin, esophagus,
or brain. Herpes simplex virus type 2 (HSV-2)
usually causes infections of the genitals, rectum, skin,