ANTIRETROVIRAL DRUGS
I. NUCLEOSIDE/NUCLEOTIDE REVERSE TRANSCRIPTASE INHIBITORS (NRTIS)
ZODOVUDINE DIDANOSINE STAVUDINE ZALCITABINE LAMIVUDINE ABACAVIR TENOVIR EMTRICITABINE
Cytosine
Synthetic Purine nucleoside Synthetic Synthetic Cytosine analog The only approved ARV Derivative of analog that is
thymidine analog cytosine analog
thymidine analog analog reverse that is a guanosine analog adenosine chemically
reverse •
transcriptase transcriptase 5′-monophosphate related to
inhibitor inhibitor lacking a complete lamivudine and
ribose ring shares many of
its properties
HIV-1, HIV-2, & HIV-1, HIV- 2, & HIV-1, HIV-2 & HIV-1 HIV-1, HIV-2, &
HIV-1 & HIV-2 HIV-1, HIV-2, & HBV HIV-1, HIV-2, & HBV
HTLV I, HTLV-2 HTLV-1 HBV reverse transcriptase HBV
Treatment of adults and ACID LABILE After entering After entering The active species is the Synthetic purine analog that It is the only • High-level host
children with HIV It is administered with the cell, it is the cell, it is is converted in the cell nucleotide analog resistance
intracellular to carbovir triphosphate
infection and for an antacid buffer phosphorylated phosphorylated occurs with the
triphosphate derivative, currently marketed for
preventing mother-to- to its active form, to its active which has low affinity for Oral bioavailability is >80% the treatment of HIV same mutation
child transmission Food decreases stavudine anabolite,
bioavailability human DNA polymerases regardless of food intake infection. (M184V) that
5′-triphosphate dideoxycytidine- affects
Recommended for Must be administered 5’-triphosphate High-level resistance Prolonged t1/2 of Poor bioavailability lamivudine
postexposure at least 30 mins Unlike Occurs with single-amino-acid carbovir triphosphate administered as sensitivity
prophylaxis in HIV- before or 2 hours zidovudine, the In addition mutations at codon 184 that (administered once daily) adisoproxil fumarate (occurs less
exposed healthcare after eating monophosphate to DNA can reduce in vitro sensitivity prodrug frequently)
workers, also in does not polymerase -
to the drug by up to 1000-fold
combination with other accumulate polymerase β § Rapidly converted to
but restore sensitivity to Mutation
antiretroviral agents within the cell zidovudine. tenofovir, which then restores
Well-absorbed sensitivity to
is phosphorylated by
Well absorbed orally and food o This effect may contribute to cellular kinases to zidovudine
Bioavailability is does not affect the sustained virologic the active metabolite,
not affected bioavailability benefits of combination tenofovir diphosphate• Excellent oral
by food therapy with absorption and
Largely lamivudine and zidovudine Primarily is excreted can be taken
Dose should be excreted unchanged in the
unchanged in without regard
adjusted in Oral bioavailability >80% urine to food
patients with renal the urine
(not affected by food)
insufficiency Excreted primarily Dose should be • It has a long
Dose must be
unchanged in the urine decreased in elimination t1/2
reduced in
patients with and can be
patients with Dose adjustment is renal insufficiency administered
impaired renal recommended for patients
function once daily and
with a creatinine clearance
excreted
of <50 mL/min
unchanged in
the urine.
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ZODOVUDINE DIDANOSINE STAVUDINE ZALCITABINE LAMIVUDINE ABACAVIR TENOVIR EMTRICITABINE
No impact in cells already After entering the cell, it is Most common Zalcitabine Few significant Most important • Few adverse events Least toxic
infected with HIV converted by phosphorylation adverse effect toxicities are effects adverse effect except for flatulence
antiretroviral
Peripheral similar to those Neutropenia, Potentially
to the active metabolite neuropathy (12%) Rare episodes of drugs and has
Most effective in activated of the other headache, and fatal hypersensitivity
dideoxyadenosine few significant
lymphocytes because the dideoxynucleotide nausea have been reaction (2-9%) acute renal failure &
5’-triphosphate adverse effects
phosphorylating enzyme, Most strongly analogs reported Fanconi’s syndrome
thymidine kinase, linked to the didanosine Typically begins within
It has long intracellular t1/2 of It is a common 6 weeks of drug initiation • Can increase the Prolonged
is S-phase specific HIV lipodystrophy and stavudine exposure has
the active anabolite, hence, component of AUC of didanosine,
syndrome been
administered Due to toxic therapy based on Characterized by fever, and the drugs
May be taken irrespective Severe peripheral probably associated with
once daily effects on its safety, abdominal pain and other GI hyper-
of food and undergoes neuropathy
rapid first-pass hepatic adipocytes (up to 15%) convenience, complaints, a maculopapular• Should not be used pigmentation
metabolism to Single codon mutations, and efficacy rash, malaise, and fatigue together
5-glucuronyl zidovudine. including TAMs contribute Combining • It is not subject
stavudine with Pancreatitis
to resistance Less common S/E to any known
zidovudine occurs rarely but • Since lamivudine
Side effects: fatigue, coadministration of and emtricitabine Respiratory complaints, metabolic drug
Most serious toxicities Leads to have nearly headache, and paresthesias Interactions
malaise, myalgia, nausea, increased risk other drugs that
Peripheral neuropathy and identical • Presence of fever, abdominal
anorexia, headache, and and severity of cause pancreatitis
pancreatitis, both due to resistance and pain, and rash within
insomnia, which generally mitochondrial toxicity peripheral should be avoided
resolve within the first few activity patterns, • 6 weeks of starting abacavir
neuropathyand is diagnostic and
weeks of therapy potentially fatal One distinctive there is no
Avoided in patients with a rationale for their necessitates immediate
Stavudine and zidovudine history of pancreatitis or pancreatitis toxicity is oral
compete for intracellular combined use drug discontinuation
neuropathy and should not ulceration and
phosphorylation and should be co-administered with other Should not be stomatitis
not be used together • Hypersensitivity syndrome
drugs that can cause used together Results from an immune
The Met-to-Val substitution neuropathy under most An erythematous reaction that is genetically
at reverse transcriptase circumstance rash is common linked to the HLA-B and the
codon 184 associated with Diarrhea is reported more but generally
Lactic acidosis heat shock protein 70 loci
use of lamivudine greatly frequently with than with self- limited
restores sensitivity to and hepatic
other nucleoside analogs, steatosis Widely used in combination
zidovudine perhaps related to the More common with other antiretroviral
antacid in the oral with stavudine agents
These drugs are often used preparations than with
in combination zidovudine or o Supplied in coformulations
The buffering agents also abacavir with zidovudine or lamivudine
can impair the bioavailability for twice-daily administration
of other co-administered and with lamivudine for
drugs once-daily administration
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