Page 247 - Hall et al (2015) Principles of Critical Care-McGraw-Hill

CHAPTER 22: Pain Control, Sedation, and Use of Muscle Relaxants 151

TABLE 22-2 Opiates
Fentanyl Morphine Hydromorphone Remifentanil
Onset 1-2 minutes 5-10 minutes 5-10 minutes 1-3 minutes
Elimination half-life 2-4 hours 3-4 hours 2-3 hours 3-10 minutes
Metabolic pathway N-dealkylation CYP3A4/5 substrate Hepatic, glucuronidation Hepatic, glucuronidation Hydrolysis by plasma esterases
Active metabolite None 6- and 3- glucuronide metabolite None None
Intermittent dosing 0.35-0.5 μg/kg IV q0.5-1h 2-4 mg IV q1-2 h 0.2-0.6 mg IV q1-2 h None
Continuous infusion 25-200 μg/h 2-30 mg/h 0.5-3 mg/h 1.5 μg/kg IV loading dose; then
0.5-15 μg/kg/h
Side effects Less hypotension; accumulation with hepatic Accumulation with hepatic/renal Accumulation with hepatic/renal No accumulation with organ
impairment impairment, histamine release impairment dysfunction, use ideal body weight

The duration of action after a single dose is approximately 4 hours. anxiolysis is also common, although less than with benzodiazepines.
As the drug is given repeatedly, accumulation in tissue stores may Opiates have no reliable amnestic properties.
prolong its effect. Morphine undergoes glucuronide conjugation Respiratory system: Opiates lead to a dose-dependent centrally medi-
in the liver and has an active metabolite, morphine-6-glucuronide. ated respiratory depression, one of the most important complications
Elimination occurs in the kidney, so effects may be prolonged in associated with their use. Respiratory depression, mediated by the
renal failure. μ receptors in the medulla, typically presents with a decreased respi-
2
Fentanyl: Fentanyl is very lipid soluble, thereby rapidly crossing the ratory rate but preserved tidal volume producing a characteristic slow
blood-brain barrier and exhibiting very rapid onset of action. Its and deep breath. The CO response curve is blunted, and the ventila-
2
duration of action after a single dose is short (0.5-1 hour) because tory response to hypoxia is obliterated. An important benefit of these
of redistribution into peripheral tissues; however, as with all opiates, drugs is the relief of the subjective sense of dyspnea frequently present
accumulation and prolongation of effect can occur when this drug is in critically ill patients with respiratory failure.
given for extended periods. Inactive products of hepatic metabolism Cardiovascular system: Opiates have little hemodynamic effect on
are excreted by the kidney. euvolemic patients whose blood pressure is not sustained by a hyper-
Hydromorphone: The onset of action is similar to morphine. The dura- active sympathetic nervous system. When opiates and benzodiaz-
tion of action is shorter than morphine when given as a single dose. epines are given concomitantly, they may exhibit a synergistic effect
The absence of active metabolites makes the duration typically shorter on hemodynamics. The reasons for this synergy are not entirely clear.
than that of morphine when administered for extended periods. Meperidine has a chemical structure similar to atropine and may elicit
However, it can still accumulate with hepatic or renal dysfunction. a tachycardia, another reason its use is discouraged in the ICU. All
Remifentanil: Remifentanil is a lipid-soluble drug with a rapid onset other opiates usually decrease heart rate by decreasing sympathetic
of action. This drug is unique in that it is metabolized rapidly via activity. Morphine and meperidine may cause histamine release,
hydrolysis by nonspecific blood and tissue esterases. As such, its although it is rarely important in doses typically used in the ICU.
70
pharmacokinetic profile is not affected by hepatic or renal insuf- Fentanyl does not release histamine. Remifentanil may cause brady-
ficiency. It must be given by continuous infusion because of its rapid cardia and hypotension, particularly when administered concurrently
recovery time. This rapid recovery, typically minutes after cessation with drugs known to cause vasodilation, such as propofol.
of the drug infusion, may be useful in the management of critically ill Other effects: Other side effects include nausea, vomiting, and decreased
patients. Because remifentanil is eliminated from the body so rapidly, gastrointestinal motility. Methylnaltrexone, a specific antagonist of μ
2
in some cases it may lead to a circumstance in which patients are left receptors in the gut, has been reported recently to attenuate this side
with no analgesia after discontinuing the infusion. Remifentanil as a effect in humans. The utility of methylnaltrexone in the ICU has not
71
component of general anesthesia may have a role in reducing the need been tested and is only recommended in patients with chronic opioid use.
for ICU admissions by allowing extubation in the operating room and Other side effects include urinary retention and pruritus. Muscle rigidity
preventing the need for postoperative ICU care. 68,69 occasionally occurs with fentanyl and remifentanil. This is seen typi-
Meperidine: Meperidine’s greater lipid solubility leads to more rapid cally when high doses of these drugs are injected rapidly and may affect
movement across the blood-brain barrier and a more rapid onset of the chest wall muscles, making ventilation impossible. Neuromuscular
action, typically 3 to 5 minutes. Because of redistribution to periph- blockade, typically with succinylcholine, reverses this problem.
eral tissues, its duration of action after a single dose is less than that Benzodiazepines: Benzodiazepines act by potentiating γ-aminobutyric
of morphine (1-4 hours). Meperidine undergoes hepatic metabolism acid (GABA) receptor complex–mediated inhibition of the CNS.
and renal elimination. A major problem with the use of meperidine The GABA receptor complex regulates a chloride channel on the cell
is its metabolite normeperidine, a CNS stimulant that can precipitate membrane, and by increasing the intracellular flow of chloride ions,
seizures, especially with renal failure and/or prolonged use. Since neurons become hyperpolarized, with a higher threshold for excit-
meperidine offers no apparent advantage over other opiates, it has ability. Flumazenil is a synthetic antagonist of the benzodiazepine
little role in the management of critically ill patients, outside of use as receptor that may reverse many of the clinical effects of benzodiaz-
an antidote for post-anesthesia shivering. epines; however, care must be taken when administering flumazenil
in patients on chronic benzodiazepines as it may precipitate seizures.
Pharmacodynamics All opiates have similar pharmacodynamic effects and
will be discussed without reference to individual drugs except where Table 22-3 presents a summary of the pharmacologic properties of the
important differences are present. benzodiazepines.
Central nervous system: The primary effect of opioids is analgesia, Pharmacokinetics The three available intravenous benzodiazepines, mid-
mediated mainly through the μ and κ receptors. Mild to moderate azolam, lorazepam, and diazepam, are discussed below.

section02.indd 151 1/13/2015 2:05:05 PM