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

by effects on the circular and longitudinal muscles of
the intestine, presumably as a result of its interactions
with opioid receptors in the intestine. Some part of its
antidiarrheal effect may be due to a reduction of gastrointestinal
secretion (described earlier) (Kromer,
1988). In controlling chronic diarrhea, loperamide is as
effective as diphenoxylate. In clinical studies, the most
common side effect was abdominal cramps. Little tolerance
develops to its constipating effect.
In human volunteers taking large doses of loperamide, concentrations
of drug in plasma peak ~4 hours after ingestion; this long
latency may be due to inhibition of GI motility and to enterohepatic
circulation of the drug. The apparent elimination t 1/2
is 7-14 hours.
Loperamide is poorly absorbed after oral administration and, in addition,
apparently does not penetrate well into the brain due to the
exporting activity of P-glycoprotein, which is widely expressed in
the brain endothelium (Sadeque et al., 2000). Mice with deletions
of one of the genes encoding the P-glycoprotein transporter have
much higher brain levels and significant central effects after
administration of loperamide (Schinkel et al., 1996). Inhibition of
P-glycoprotein by many clinically used drugs, such as quinidine
and verapamil, possibly could lead to enhanced central effects of
loperamide.
In general, loperamide is unlikely to be abused parenterally
because of its low solubility; large doses of loperamide given to
human volunteers do not elicit pleasurable effects typical of opioids.
The usual dosage is 4-8 mg/day; the daily dose should not
exceed 16 mg.
FENTANYL AND CONGENERS
Fentanyl
Fentanyl is a synthetic opioid related to the
phenylpiperidines (Figure 18–9). The actions of fentanyl
and its congeners, sufentanil, remifentanil, and alfentanil,
are similar to those of other MOR agonists. Alfentanil
(ALFENTA, others) is seldom used. Fentanyl and sufentanil,
are very important drugs in anesthetic practice
because of their relatively short time to peak analgesic
effect, rapid termination of effect after small bolus doses,
minimal direct depressant effects on the myocardium,
and their ability to significantly reduce the dosing
requirement for the volatile agents (“MAC-sparing”; see
Chapter 19). In addition to a role in anesthesia, fentanyl
also is used in the management of severe pain states.
Pharmacological Properties
CNS Effects. Fentanyl and its congeners are all extremely potent analgesics
and typically exhibit a very short duration of action when
given parenterally. As with other opioids, nausea, vomiting, and itching
can be observed. Muscle rigidity, while possible after all narcotics,
appears to be more common after the high doses used in
anesthetic induction. Rigidity can be treated with depolarizing or
non-depolarizing neuromuscular blocking agents while controlling
the patient’s ventilation. Care must be taken to make sure that the
patient is not simply immobilized but aware. Respiratory depression
is similar to that observed with other receptor agonists, but the onset
is more rapid. As with analgesia, respiratory depression after small
doses is of shorter duration than with morphine but of similar duration
after large doses or long infusions. As with morphine and
meperidine, delayed respiratory depression also can be seen after the
use of fentanyl or sufentanil, possibly owing to enterohepatic circulation.
High doses of fentanyl can cause neuroexcitation and, rarely,
seizure-like activity in humans (Bailey and Stanley, 1994). Fentanyl
has minimal effects on intracranial pressure when ventilation is controlled
and the arterial CO 2
concentration is not allowed to rise.
Cardiovascular System. Fentanyl and its derivatives decrease heart
rate and mildly decrease blood pressure. However, these drugs do
not release histamine and direct depressant effects on the
myocardium are minimal. For this reason, high doses of fentanyl or
sufentanil are commonly used as the primary anesthetic for patients
undergoing cardiovascular surgery or for patients with poor cardiac
function.
Absorption, Distribution, Metabolism, and Excretion. These agents
are highly lipid soluble and rapidly cross the blood-brain barrier.
This is reflected in the t 1/2
for equilibration between the plasma and
cerebrospinal fluid of ~5 minutes for fentanyl and sufentanil. The
levels in plasma and cerebrospinal fluid decline rapidly owing to
redistribution of fentanyl from highly perfused tissue groups to other
tissues, such as muscle and fat. As saturation of less well-perfused
tissue occurs, the duration of effect of fentanyl and sufentanil
approaches the length of their elimination t 1/2
, 3-4 hours. Fentanyl
and sufentanil undergo hepatic metabolism and renal excretion. With
the use of higher doses or prolonged infusions, the drugs accumulate,
these clearance mechanisms become progressively saturated, and
fentanyl and sufentanil become longer acting.
Therapeutic Uses. Fentanyl citrate (SUBLIMAZE, others) and sufentanil
citrate (SUFENTA, others) have widespread popularity as anesthetic
adjuvants (Chapter 19). They are used commonly either
intravenously, epidurally, or intrathecally. The analgesic effects of
fentanyl and sufentanil are similar to those of morphine and other
opioids. Fentanyl is ~100 times more potent than morphine, and
sufentanil is ~1000 times more potent than morphine. The time to
peak analgesic effect after intravenous administration of fentanyl
and sufentanil (~5 minutes) is notably less than that for morphine
and meperidine (~15 minutes). Recovery from analgesic effects also
occurs more quickly. However, with larger doses or prolonged infusions,
the effects of these drugs become more lasting, with durations
of action becoming similar to those of longer-acting opioids
(described later). Intravenous use of fentanyl and sufentanil for postoperative
pain has been popular.
Epidural use of fentanyl and sufentanil for postoperative or
labor analgesia has significant popularity. A combination of epidural
opioids with local anesthetics permits reduction in the dosage of both
components, minimizing the side effects of the local anesthetic (i.e.,
motor blockade) and the opioid (i.e., urinary retention, itching, and
delayed respiratory depression in the case of morphine). An important
caveat to their spinal use is that because of their rapid clearance,
these agents at analgesic spinal doses can produce blood levels that
are similar to those producing effects after systemic administration
(Bernards, 2004).
505
CHAPTER 18
OPIOIDS, ANALGESIA, AND PAIN MANAGEMENT