cidofovir
nucleoside analog with inhibitory activity against herpes, papilloma, polyoma, pox, and
adenoviruses. IV formulation used for treatment of CMV retinitis in HIV+ patients*.
Increases the time to progression of CMV retinitis. Has been used in ACV resistant HSV
infections. Inhibits viral DNA synthesis by terminating chain elongation. Doesn't need to
be converted first to mono by virus like acyclovir, instead already diphosphate that acts
as alternative substrate for viral DNA polymerase.
RNA virus entry and replication
virus binds to cell and forms an endosome. Capsid protects itself. M2 protein allows for
hydrogen ions to come in and change the pH of the endosome which causes
degradation. The uncoating allows the virus to enter the nucleus and begin translation
into proteins. They also reproduce and release from the cell to go to the next one.
amantidine and rimantidine
anti-influenza agent. Inhibition of an early step in viral replication - the viral uncoating.
The primary target is the M2 protein. It interferes with its function and inhibit H+
dissociation of the endosome. Activity against Influenza A only*! Seasonal prophylaxis
offers 70-90% protection against it. Treatment within 2 days of onset of symptoms
reduces the duration and fever. CNS side effects (dose related). Neurotoxicity increases
with concomitant use of antihistamines and other psychotropic drugs. Widespread
resistance due to over-use.
oseltamivir and zanamivir
anti-influenza agent. These inhibit influenza neuraminidase - an enzyme that destroys
receptors present on the cell surface. This blocks the whole last step in the process of
viral replication and budding. Neuraminidase is needed to cleave the receptors to allow
the virion to go and affect the next cell. These drugs block the cleavage of this.
Treatment and prevention of both Influenza A and B infections. Pregnancy category C.
No drug interactions. Widespread resistance due to overuse. Good to use this with
amantidine to prevent resistance build up.
hepatitis C infections
common chronic infection. Prolific RNA virus. Does not integrate into chromosomal
DNA> Current standard of care (interferon alpha and ribavirin) produce high cure rates
on only select virus phenotypes.
hepatitis B infections
transcribed into DNA and can be integrated into the host chromosome. Establishes a
lifelong chronic infection (10%). Interferon treatment can cure infections but is
associated with extensive side effects.
interferons
as anti-hepatitis agents; potent cytokines that have antiviral activity. Synthesized by the
host cell in response to inducers. Alpha, beta, and gamma major classes. All play some
role in antiviral response in the cell. *Clinically, recombinant alpha version of this
predominate in US market! We produce these ourselves!
ribavirin
anti-hepatitis agent; nucleoside analog that inhibits replications of a wide range of RNA
and DNA viruses. Mechanisms not completely defined, but alters cellular pools of
nucleotides and inhibits viral mRNA. Has multiple sites of action to inhibit nucleic acid
synthesis. No resistance documented. Used in combo with interferon as standard of
treatment for chronic HCV infection. Won't cure Hep C, but will reduce levels of viral
load.
adverse effects of ribavirin
dose limiting toxicities include dose-related anemia, bone marrow suppression,
oxidative damage to cell membranes, pregnancy category X (causes malformation of
embryo)!!! Inhibits antiviral activity of HIV-pyrimidine reverse transcriptase inhibitors (like
zidovudine) and increases the activity of HIV-purine reverse transcriptase inhibitors.
HIV
RNA viruses that establish chronic persistent infections with gradual onset of clinical
symptoms. Replication of this is constant. Infected cells can also harbor non-replicating
virus for years. Pharmacotherapy for this is dynamic-three drug minimum is current
standard of care. Cannot use monotherapy because it is the master of mutation.
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HIV life cycle
HIV will dock and then fuse into the cell. Virion genomic RNA will go through reverse
transcription that turns into DNA. The proviral DNA will get incorporated into host
chromosome. It can undergo transcription that will translate into structural and
regulatory or become latent. Ultimately a mature virion will be produced and affect
another cell.
HIV chemotherapy
goal is to suppress viral replication as much as possible for as long as possible. HIV+
pregnant women receiving antiretrovirals prevent virus transmission to the fetus.
Reservoirs of long-lived quiescent T-cells harboring infectious HIV DNA integrated into
the host chromosome (non replicating form) is not targeted by anti-retrovirals and so
eradication remains elusive. Drug resistance is a significant problem. HIV has a high
mutation rate, monotherapy promotes emergence of resistant viruses.
reverse transcriptase (RT)
RNA dependent DNA polymerase that converts viral RNA into proviral DNA for
incorporation into host chromosome.
nucleoside RT inhibitors
antiretroviral. Prevents infection of susceptible cells but does not eradicate virus from
cells that harbor integrated proviral DNA. These enter cell and undergo phosphorylation.
Triphosphorylated forms of analogs then block replication by inhibiting incorporation of
native nucleotides and then terminating elongation of proviral DNA. Block HIV DNA from
being produced by binding to active site of enzyme and preventing DNA synthesis. Kind
of works similarly to acyclovir.
non-nucleoside inhibitors
antiretroviral. Bind to hydrophobic pocket in HIV reverse transcriptase. This pocket is
non essential for enzyme function. Induces 3-D conformational change that reduces
enzyme activity. Non competitive inhibitor of RT! Do not require intracellular
phosphorylation. No activity against DNA polymerase. Renders the enzyme ineffective.
May cause severe fatal hepatitis and CNS/psychiatric side effects. Drug interactions by
causing lowered plasma concentrations of CYP3A4 substrates*! High level resistance
from single amino acid substitutions in that binding site. Can induce resistance and
virologic relapse in days if given as monotherapy. Potent agents but MUST be combined
with two other active agents.
HIV protease inhibitors
really big molecules; competitive inhibitors of HIV aspartyl . Prevent proteolytic
cleavage of HIV precursor polypeptides. Prevents viral maturation to infectious
form. Adverse effects - fatal hepatotoxicity has been reported with some
analogs. Crystalluria and nephrolithiasis stemming from poor drug solubility. Drug
interactions with substrates and inhibitors of CYPs. Primary resistance in enzymatic
active site, secondary mutations distant to active site lead to reduced proteolytic
efficiency.
HIV entry inhibitors - enfuvirtide
derived from part of HIV membrane (gp41 region). Inhibits fusion of virus particle to the
cell membrane. Blocks interaction of HIV and the CD4 receptor. Investigated originally
as a possible vaccine component due to high degree of sequence conservation of the
component between HIV strains.
HIV integrase inhibitors - raltegravir
prevents the formation of covalent bonds between host and viral DNA by blocking the
catalytic activity if HIV integrase. Prevents virus integration into host chromosome.
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