Clinical Manual for Management of the HIV-Infected ... - myCME.com

Section 4—Complications of Antiretroviral Therapy | 4–29
Benzodiazepines, Group I (alprazolam, clorazepate, clonazepam, diazepam, midazolam, triazolam)
These agents are
metabolized extensively
in the liver by CYP3A4
isoenzymes.
Drugs inhibiting CYP3A4 could
theoretically interfere with
metabolism of these agents, causing
a large increase in the area under
the time-concentration curve (AUC).
Ritonavir is the most potent CYP3A4
inhibitor.
Benzodiazepines, Group II (lorazepam, oxazepam, temazepam)
These benzodiazepines
are metabolized
primarily by conjugation
with glucuronic acid,
which is mediated by
glucuronosyltransferase
enzymes.
Caffeine
Thought to be
extensively metabolized
by the CYP1A2 enzyme
group. Minor pathways
include CYP2D6 and
CYP3A4.
Cocaine
Primarily metabolized
by tissue and plasma
enzymes. Small amount
(10%) is metabolized
by P450 enzymes
(CYP3A3/4, CYP2B1) to
hepatotoxic metabolite.
Cocaine may induce
some P450 enzymes with
chronic use, and inhibit
others with acute use.
The isoenzymes involved
are not related to ARV
drug metabolism.
Agents that increase
glucuronosyltransferase enzyme
activity may increase the metabolism
of these compounds. Ritonavir may
increase the metabolism of these
drugs by this mechanism.
Drugs most likely to affect the
metabolism of caffeine include those
that inhibit its major metabolizing
isoenzymes: ciprofloxacin (and
potentially other fluoroquinolones)
and macrolide antibiotics.
Potential interaction with:
•
•
•
Protease inhibitors (PIs)
Nonnucleoside reverse transcriptase
inhibitors (NNRTIs) (nevirapine,
efavirenz)
Macrolide antibiotics (erythromycin,
clarithromycin)
Large increases in the AUC (>3-fold)
of some of these compounds could
have serious consequences, including
sedation and respiratory depression.
Concomitant use of these agents
with ritonavir may decrease their
therapeutic effectiveness. In patients
who are abusing these agents,
reduction in serum levels may cause
symptoms of withdrawal, including:
rebound insomnia, tremors,
irritability, dysphoria, panic/paranoia,
and convulsions.
Elevations in caffeine levels may result
in accentuated effects: increased
blood pressure, increased central
nervous system stimulation, tremors,
and atrial dysrhythmias. CYP3A4
inhibitors such as ritonavir potentially
elevate caffeine levels, but this is
unlikely as it involves a very minor
pathway in caffeine metabolism.
Both inhibition and induction of
P450 enzymes can lead to increased
effects or toxicities of cocaine because
of increased levels of the drug or
active metabolites. However, given
the minor role these enzymes play in
overall cocaine metabolism, clinical
significance is unlikely.
Cocaine is unlikely to have any
significant effects on ARV agents.
Midazolam and triazolam are
contraindicated for use with ritonavir;
other PIs should be used with extreme
caution. Other benzodiazepines may be
administered safely with PIs, with close
monitoring and dose adjustment.
Patients receiving these benzodiazepine
agents for therapeutic purposes should
be monitored for loss of effectiveness in
the presence of ritonavir therapy.
These benzodiazepine agents are likely
to have less toxicity than the above
(group I) agents.
Patients who are known to be actively
abusing these agents should be given
an alternate PI or monitored for
withdrawal.
Recommend decreasing caffeine intake
while concomitantly using agents
that inhibit CYP1A2. No documented
interaction between caffeine and PIs
has been reported.
Monitor for increased cocaine effects
and hepatotoxicity.
Cocaine is also a known immunotoxic
agent, significantly decreasing CD4 +
cell production by as much as 3- to
4-fold, and increasing the rate of HIV
reproduction up to 20-fold.