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

512 syndrome in patients dependent on pentazocine, butorphanol,
or nalbuphine. Naloxone produces overshoot
phenomena suggestive of early acute physical dependence
6-24 hours after a single dose of an μ agonist
(Heishman et al., 1989). In dependent patients, peripheral
side-effects, notably reduced GI motility and constipation,
can be reversed by methylnaltrexone with
doses of 0.15 mg/kg subcutaneously, producing reliable
bowel movements and no evidence of centrally mediated
withdrawal signs (Thomas et al., 2008).
SECTION II
NEUROPHARMACOLOGY
Absorption, Distribution,
Metabolism, and Excretion
Although absorbed readily from the GI tract, naloxone
is almost completely metabolized by the liver before
reaching the systemic circulation and thus must be
administered parenterally. The drug is absorbed rapidly
from parenteral sites of injection and is metabolized in
the liver primarily by conjugation with glucuronic acid;
other metabolites are produced in small amounts. The
t 1/2
of naloxone is ~1 hour, but its clinically effective
duration of action can be even less.
Compared with naloxone, naltrexone retains much more of its
efficacy by the oral route, and its duration of action approaches 24
hours after moderate oral doses. Peak concentrations in plasma are
reached within 1-2 hours and then decline with an apparent t 1/2
of
~3 hours; this value does not change with long-term use. Naltrexone
is metabolized to 6-naltrexol, which is a weaker antagonist but has
a longer t 1/2
, ~13 hours. Naltrexone is much more potent than naloxone,
and l00 mg oral doses given to patients addicted to opioids produce
concentrations in tissues sufficient to block the euphorigenic
effects of 25-mg intravenous doses of heroin for 48 hours (Gonzalez
and Brogden, 1988). Methylnaltrexone is handled similarly to naltrexone.
It is converted to methyl-6-naltrexol isomers and is largely
eliminated primarily as the unchanged drug with significant active
renal secretion. The terminal disposition t 1/2
of methylnaltrexone is
~8 hours.
Therapeutic Uses
Treatment of Opioid Overdosage. Opioid antagonists, particularly
naloxone, have an established use in the treatment of opioid-induced
toxicity, especially respiratory depression. Its specificity is such that
reversal by this agent is virtually diagnostic for the contribution of
an opiate to the depression. Naloxone acts rapidly to reverse the respiratory
depression associated with high doses of opioids. It should
be used cautiously because it also can precipitate withdrawal in
dependent subjects and cause undesirable cardiovascular side effects.
By carefully titrating the dose of naloxone, it usually is possible to
rapidly antagonize the respiratory-depressant actions without eliciting
a fully expressed withdrawal syndrome. The duration of action
of naloxone is relatively short, and it often must be given repeatedly
or by continuous infusion. Opioid antagonists also have been
employed effectively to decrease neonatal respiratory depression
secondary to the intravenous or intramuscular administration of opioids
to the mother. In the neonate, the initial dose is 10 μg/kg given
intravenously, intramuscularly, or subcutaneously.
Management of Constipation. The peripherally limited antagonists
such as methylnaltrexone have a very important role in the management
of the constipation and the reduced GI motility present in the
patient undergoing chronic opioid therapy (as for chronic pain or
methadone maintenance) and have been approved by the FDA for
that use. With distribution restricted to the periphery, these agents
do not alter central opioid agonist actions. Worrisome reports of GI
perforation in this setting are under review by FDA. Other strategies
for the management of opioid-induced constipation are described in
Chapter 46.
Management of Abuse Syndromes. There is considerable interest
in the use of opiate antagonists such as naltrexone as an adjuvant in
treating a variety of non-opioid dependency syndromes such as alcoholism
(Chapters 23 and 24), where an opiate antagonist decreases
the chance of relapse (Anton, 2008). Interestingly, patients with a
single nucleotide polymorphism (SNP) in the MOR gene have significantly
lower relapse rates to alcoholism when treated with naltrexone
(Haile et al., 2008). Naltrexone is FDA-approved for
treatment of alcoholism.
Trauma. The potential utility of opiate antagonists in the treatment
of shock, stroke, spinal cord and brain trauma, and other disorders
that may involve mobilization of endogenous opioid peptides has
been reported; but opioid antagonists have failed to demonstrate
neuroprotective benefits and their study in trauma has been largely
abandoned (Hawryluk et al., 2008).
CENTRALLY ACTIVE ANTITUSSIVES
Cough is a useful physiological mechanism that serves
to clear the respiratory passages of foreign material and
excess secretions. It should not be suppressed indiscriminately.
There are, however, many situations in
which cough does not serve any useful purpose but
may, instead, annoy the patient, prevent rest and sleep,
or hinder adherence to otherwise beneficial medication
regimens (e.g., angiotension-converting enzyme (ACE)
inhibitor-induced cough). Chronic cough can contribute
to fatigue, especially in elderly patients. In such situations,
the physician should try to substitute a drug with
a different side effect profile (e.g., an AT 1
antagonist in
place of an ACE inhibitor) or add an antitussive agent
that will reduce the frequency or intensity of the coughing
(Chapters 12 and 36).
A number of drugs reduce cough as a result of
their central actions, including opioid analgesics
(codeine, hydrocodone, and dihydrocodeine are the opioids
most commonly used to suppress cough). Cough
suppression often occurs with lower doses of opioids
than those needed for analgesia. A 10- or 20-mg oral
dose of codeine, although ineffective for analgesia,