- Zidovudine (azidothymidine, AZT):
- activation by
phosphorylation to the 5'-triphosphate
derivative; phosphorylated by three
cellular kinases;
- active drug is a
competitive inhibitor of deoxythymidine triphosphate;
- active drug also
chain-terminates proviral DNA synthesis.
- Activity (in vitro) against: HIV-1,
HIV-2, human T cell lymphotrophic viruses;
- weaker activity:
hepatitis B virus, Epstein-Barr virus.
- Resistance: reverse transcriptase
gene mutations;
- resistance more frequent in
advanced HIV infection;
- Mutations at certain codons
associated with 100-fold reduction in
viral susceptibility to zidovudine.
- Multiple mutations result in
additive loss of drug susceptibility.
- Oral and IV formulations available
- Significant first pass effect
results in a bioavailability of about 65%.
- Hepatic disease
(cirrhosis) reduces the clearance
significantly and requires dosage
adjustment.
- Renal disease may
also require dosage adjustment.
Zidovudine:
Clinical Use
- Zidovudine inhibits HIV-1
replication and may decrease of the rate of
disease progression and may prolong survival.
- Effective in treating: HIV
encephalopathy; HIV thrombocytopenia;
- Zidovudine (Retrovir, AZT,
azidothymidine) may be hidden in combination with
any other nRTIs [except for stavudine (Zerit,
d4T)]
- Zidovudine (Retrovir, AZT,
azidothymidine) plus stavudine (Zerit,
d4T) causes antagonism
- Resistance to zidovudine
(Retrovir, AZT, azidothymidine): increasing in
newly infected patients & those previously
treated with the drug.
- Effective
in prevention of mother to newborn transmission
of HIV.
- Combination
of zidovudine with other agents, including
additional reverse transcriptase inhibitor or
protease inhibitor appears to enhance antiviral
activity while decreasing development of
resistance.
- ZDV is beneficial for AIDS
patients-- probably associated with prolonged
survival and decreases in frequency and severity
of opportunistic infections.
- ZDV was also shown
beneficial in clinical trials involving patients
with less severe disease, including patients with
early symptomatic disease or asymptomatic
patients with CD4 counts < 500 per ml.
- ZDV monotherapy is
inferior to its use in combination with other
antiretroviral drugs.
- Generally, monotherapy is
no longer recommended in view of the
success of combination protocols.
- Possibly due to the
development of resistance, ZDV clinical efficacy
diminishes after 12-18 months.
- The rationale for ZDV
administration in combination with other agents
is that such combinations may diminish or modify
the emergence of resistant viral strains.
- Zidovudine plus lamivudine
often with a protease inhibitors -- recommended
for HIV prevention after a needle stick or sexual
exposure.-Morbidity and Mortality Weekly Report,
47, RR7: 1, 1998
- ZDV available in combination with
lamivudine as Combivir.
- ZDV not associated with fetal
malformations, if taken after first trimester
pregnancy (medical letter 12/12/97)
Zidovudine:
Adverse reactions
- Most common: myelosuppression
(anemia, neutropenia) -- myelosuppression may be
worse is the zidovudine is administered with
other drugs that the also cause bone marrow
suppression.
- Lactic acidosis -- rare, but can
be fatal.
- transient adverse reactions,
resolving with continued use, include GI
intolerance, headache, insomnia.
- Less frequent side effects:
thrombocytopenia, myopathy, acute cholestatic
hepatitis:
- High-dose zidovudine therapy may
cause CNS effects: confusion, anxiety,tremulousness.
Zidovudine:
Drug-Drug Interactions
- Zidovudine dosage adjustment
required if coadministered with drugs that
inhibit hepatic glucuronidation (and probenecid
(Benemid), naproxen (Naprosyn, Aleve), phenytoin
(Dilantin), beta-lactam antibiotics,
phenobarbital, ethinyl estradiol)
- Increase zidovudine toxicity may
also be caused by concurrent administration of
drugs that are hepatically metabolized
(acetaminophen, cimetidine (Tagamet), methadone,
sulfonamides, benzodiazepines)
- Zidovudine administration may
decrease levels of the anti-epileptic drug
phenytoin (Dilantin)-- requiring serum phenytoin
level monitoring.
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